KR100485525B1 - 변형된 혈액응고인자 ⅷ - Google Patents
변형된 혈액응고인자 ⅷ Download PDFInfo
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- KR100485525B1 KR100485525B1 KR10-2002-7011843A KR20027011843A KR100485525B1 KR 100485525 B1 KR100485525 B1 KR 100485525B1 KR 20027011843 A KR20027011843 A KR 20027011843A KR 100485525 B1 KR100485525 B1 KR 100485525B1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/10—Factor VIII, AHF; related peptides
Abstract
본 발명은 B-도메인이 소실된 변형된 돼지 혈액응고인자 Ⅷ, 이를 인코딩하는 DNA 서열 및 혈우병 치료를 위한 이의 용도에 관한 것이다.
Description
도 1A 내지 1H는 인간, 돼지, 마우스의 혈장유래인자 Ⅷ의 아미노산 서열을 상호 비교한 것이다.
혈소판이 병변이 발생한 곳에서 손상된 혈관벽에 부착하게 되면 혈액응고가 진행되기 시작한다. 효소에 의해서 조절되는 일련의 연쇄반응(cascade)을 통해서, 가용성의 피브리노겐(fibrinogen)은 트롬빈(thrombin) 효소의 작용에 의해서 불용성 피브린으로 전환되고, 결과적으로 피브린은 부착된 혈소판과 함께 혈전을 형성한다. 이러한 혈액응고를 유발하는 연쇄반응의 각 단계에서 단백질 전구체는 다음 단계의 단백질 전구체를 절단할 수 있는 단백질분해효소(protease)로 전환되어 활성화되고, 대부분의 단계는 조효소(cofactor)를 필요로 한다.
혈액응고인자 Ⅷ(인자 Ⅷ, factor Ⅷ)은 불활성 전구체의 형태로, 즉 폰 빌레브란트 인자(von Willebrand factor, vWF)에 비공유적으로 강하게 결합된 형태로 혈액 내에서 순환한다. 혈액응고인자 Ⅷ은 트롬빈 또는 혈액응고인자 Xa에 의해서 촉매되는 단백질 분해반응에 의해서 활성화되고, 이때, vWF로부터 분리되어 활성화됨으로써 전혈액응고제(procoagulant)의 활성을 갖게된다. 활성화된 형태의 혈액응고인자 Ⅷ은 혈액응고인자 X의 활성화를 촉매하는 역할을 수행하는 혈액응고인자 Ⅸa의 활성을 증가시키는 조효소로서 작용한다.
혈액응고인자 Ⅷ가 결핍되어 있거나 이에 대한 항체를 가지고 있는 사람은 혈액응고인자 Ⅷ로 치료하기 힘들고, 내부 출혈시 조절이 되지 않아서 관절에서 염증반응을 유발하거나 초기에 사망하는 등의 심각한 상태까지 진전될 수 있다. 미국에서 약 10,000명에 이르는 사람이 심각한 혈우병환자로 알려져 있으며, 이러한 환자는 인간혈액응고인자 Ⅷ를 충분한 농도로 투여받음으로써 정상적인 혈액응고반응을 회복할 수 있다. 혈액응고인자 Ⅷ는 원래 혈우병 A 환자의 혈장에서 혈액응고의 이상을 교정해 주는 데 사용된 정상 혈장에 존재하는 물질에서 유래한 것이다.
혈액응고인자 Ⅷ(또는 혈장유래인자 Ⅷ)의 활성을 억제할 수 있는 항체(억제인자 또는 억제작용을 하는 항체)는 혈우병 환자에서 생성될 수 있고, 이는 혈우병 환자를 치료하는 데 있어서 심각하고 복잡한 문제를 야기한다. 혈우병 A 환자의 약 20%의 경우 투여된 혈액응고인자 Ⅷ에 반응하여 이에 대한 항체가 생성된다. 혈우병 A 환자는 혈액응고인자 Ⅷ의 투여를 통한 치료시 보통 1년 이내에 억제인자(inhibitor)가 생성된다. 또한, 혈액응고인자 Ⅷ의 농도가 정상적으로 유지되는 사람에서 때때로 혈액응고인자 Ⅷ을 불활성시킬 수 있는 자가항체(autoantibody)가 형성된다. 이러한 억제인자의 역가(활성)가 충분히 낮다면, 혈액응고인자 Ⅷ의 투여량(dose)을 증가시켜 환자를 치료할 수 있다. 그러나, 억제인자의 역가는 아주 높기 때문에 혈액응고인자 Ⅷ를 이용한 치료는 불가능하다. 하나의 대안은 혈액응고인자 Ⅸ 복합체 제제(예, KONYNER, ProplexR)를 이용하여 항상성을 유지하는 동안에 혈액응고인자 Ⅷ을 요구하는 단계를 우회하는 것이다. 또한, 돼지의 혈액응고인자 Ⅷ는 일반적으로 인간 혈액응고인자 Ⅷ보다 억제인자와의 반응성이 충분히 낮기 때문에, 부분적으로 정제한 돼지의 혈액응고인자 Ⅷ 제제(HYATE:CR)를 사용하였다. 인간 혈액응고인자 Ⅷ에 대한 억제작용을 하는 항체를 가지고 있는 환자의 상당수는 돼지의 혈액응고인자 Ⅷ을 이용하여 성공적인 치료효과를 나타냈고, 장기간의 치료에도 내성이 나타났다. 그러나, 돼지의 혈액응고인자 Ⅷ를 일회 이상 투여받은 환자에서 돼지의 혈액응고인자 Ⅷ에 대한 억제인자가 형성되는 경우가 있기 때문에, 이와 같이 투여되는 돼지의 혈액응고인자 Ⅷ은 완전한 용액이라고 할 수 없다.
혈우병 A 환자의 치료에 이용될 수 있는 것으로 몇 개의 인간 혈장유래인자 Ⅷ 제제가 판매되고 있고, 이들의 정제도는 다양하다. 이러한 제제는 많은 기증자의 혈액을 모아서 열처리 및 계면활성제로 처리하여 바이러스를 사멸시킨 후 부분적으로 정제된 혈장유래인자 Ⅷ을 포함하는 있으나, 상당한 양의 항원성 단백질을 포함하고 있다. 또한, 다른 단일클론 항체를 이용하여 정제된 혈장유래인자 Ⅷ을 함유하는 시판 제제는 항원성 물질의 농도를 저하시킨 것이다. 더욱이, 재조합 인간 혈장유래인자 Ⅷ을 이용한 임상적인 치료가 시도되고 있다. 그러나, 인간 혈장유래인자 Ⅷ는 생리적 농도 및 pH에서 불안정하고, 혈액에서 아주 낮은 농도 (0.2 ㎍/ml 혈장)로 존재하며, 혈액응고에 대해 낮은 활성을 갖는다. 이러한 바이러스 감염의 위험성 및 그 외 혈액에 존재하는 오염물질 때문에, 돼지 혈액에서 정제한 돼지 혈장유래인자 Ⅷ의 임상적 이용은 제한된다.
혈우병 환자는 출혈과 이로 인한 변형된 혈우병성 관절증을 예방하기 위하여 매일 혈장유래인자 Ⅷ을 보충받아야 한다. 그러나, 혈장유래인자 Ⅷ의 공급은 불충분하고, 치료목적으로 사용하기 위해서 혈장유래인자 Ⅷ의 분리와 정제, 면역능 및 AIDS와 간염에 걸릴 위험성을 제거해야 된다는 점에서 어려운 점이 많다. 재조합 인간 혈장유래인자 Ⅷ 또는 부분적으로 정제한 돼지의 혈장유래인자 Ⅷ을 사용한다 하더라도 이러한 문제점이 모두 해결되지는 않는다.
통상적으로 사용되고 구매가능한 혈장유래인자 Ⅷ가 갖고 있는 이와 같은 문제점을 해결하여 더 우수한 혈장유래인자 Ⅷ을 개발하는 데 관심이 집중되고 있다. 즉, 분자당 더 높은 단위(unit)의 혈액응고 활성(clotting activity)이 전달될 수 있도록 좀 더 강력한 혈장유래인자 Ⅷ, 선택적 pH 및 생리적 농도에서 안정한 혈장유래인자 Ⅷ, 억제작용을 하는 항체의 생성을 유도하지 않는 혈장유래인자 Ⅷ, 인간 혈장유래인자 Ⅷ에 대한 항체를 이미 갖고 있는 환자에서 이러한 항체에 의해서 불활성화되지 않는 혈장유래인자 Ⅷ에 대한 개발이 요구되고 있다.
발명의 개요
따라서, 본 발명은 인자 Ⅷ (혈액응고인자 Ⅷ)가 결핍된 환자 또는 인간 Ⅷ에 대한 억제인자를 갖고 있는 환자에서 혈우병을 치료할 수 있는 인자 Ⅷ을 제공하는 것을 목적으로 한다.
또한, 본 발명은 혈우병 환자를 치료하는 방법을 제공하는 것을 목적으로 한다.
또한, 본 발명은 선택적 pH 및 생리적 농도에서 안정한 인자 Ⅷ을 제공하는 것을 목적으로 한다.
또한, 본 발명은 인간 인자 Ⅷ보다 응집활성(coagulant activity)이 더 높은 인자 Ⅷ을 제공하는 것을 목적으로 한다.
또한, 본 발명은 항체가 잘 생성되지 않는 인자 Ⅷ을 제공하는 것을 목적으로 한다.
더욱이, 본 발명은 재조합 돼지 인자 Ⅷ 및 특정 부분이 변형된 돼지 인자 Ⅷ을 제조하는 방법을 제공하는 것을 목적으로 한다.
도 1A 내지 1H는 인간, 돼지, 마우스의 혈장유래인자 Ⅷ의 아미노산 서열을 상호 비교한 것이다.
본 발명의 한 측면에 있어서, 돼지 인자 Ⅷ을 인코딩하는 전체 DNA 서열을 결정한 후, 우선 돼지 인자 Ⅷ을 인코딩하는 DNA 분자를 적당한 숙주세포내에서 발현시킴으로써 전장 돼지 인자 Ⅷ의 합성함으로써, 정제된 재조합 돼지 인자 Ⅷ을 제공한다. 돼지 인자 Ⅷ의 각 도메인(domain) 및 이들의 단편을 인코딩하는 DNA 분자는 이와 유사하게 발현될 수 있다. 더욱이, 본 발명은 돼지 인자 Ⅷ을 인코딩하는 DNA 분자에서 B 도메인에 있는 한 개 이상의 코돈을 소실시킨 후 발현시킴으로써, B 도메인의 전부 또는 일부가 소실된 돼지 인자 Ⅷ(B-domainless porcine fⅧ)을 제공한다.
또한 본 발명은 재조합 돼지 인자 Ⅷ 또는 변형된 재조합 돼지 인자 Ⅷ, 특히 B 도메인이 소실된 돼지 혈장유래인자 Ⅷ을 투여하는 것을 포함하는 인자 Ⅷ이 결핍된 환자 치료용 약제학적 조성물 및 치료방법을 제공한다.
특이사항이나 별다른 언급이 없으면, 본 발명에서 사용된 "인자 Ⅷ(factor Ⅷ)"은 포유동물에서 유래한 기능이 있는 인자 Ⅷ 단백질을 의미한다.
본 발명에서 사용된 "포유동물 인자 Ⅷ(mammalian factor Ⅷ)"은 별다른 특이사항이 없으면 인간을 제외한 포유동물에서 유래한 아미노산 서열을 가진 혈장유래인자 Ⅷ을 포함한다. 본 발명에서 사용된 "동물(animal)"은 돼지 및 인간을 제외한 포유동물을 의미한다.
본 발명에서 사용된 "융합 단백질(fusion protein)" 또는 "융합 인자 Ⅷ 또는 이들의 단편"은 하나의 단백질을 코딩하는 서열에 변화가 일어난 혼성유전자(hybrid gene)의 산물이다. 예를 들면, 다른 유전자에서 유래한 제2 단백질을 코딩하는 서열을 융합 단백질을 인코딩하는 혼성유전자의 전사 및 번역에 영향을 끼치지 않도록 적절한 ORF(open reading frame)을 유지하면서 다른 단백질에 삽입될 수 있다.
본 발명에서 사용된 "대응하는(또는 일치하는, corresponding)" 핵산 또는 아미노산 또는 이들의 서열은 다른 종에서 유래한 인자 Ⅷ의 일부분과 동일한 구조 및/또는 기능을 가지는 인자 Ⅷ 분자 또는 이의 단편의 일부분에 존재하고, 이때 핵산 또는 아미노산의 번호는 동일하지 않을 수 있다. 다른 인자 Ⅷ의 서열에 "대응하는 (corresponding to)" DNA 서열은 실질적으로 이러한 서열과 대응하고, 엄격한 조건에서 서열번호(SEQ ID NO.)에 명시된 서열과 혼성화한다. 또한, 다른 인자 Ⅷ의 서열에 "대응하는 (corresponding to)" DNA 서열은 인자 Ⅷ 또는 이의 단편의 발현을 결정짓는 서열을 포함하고, 서열번호에 명시된 서열과 혼성화할 수 있다. 그러나 이는 유전암호(genetic code)의 중복성(redundancy)에 의한 것이 아니다.
본 발명에서 사용된 "유일한(unique)" 아미노산 잔기 또는 서열은 한 종의 인자 Ⅷ의 아미노산 잔기 또는 서열이 다른 종에서 유래한 인자 Ⅷ의 동종성 잔기 또는 서열과 다르다는 것을 의미한다.
본 발명에서 사용된 "비활성(specific activity)"은 인간 인자 Ⅷ가 결핍된 혈장의 응집결함을 교정하는 활성을 의미한다. 비활성은 인간 인자 Ⅷ가 결핍된 혈장에서 혈액이 응고하는 데 걸리는 시간을 사람의 정상 혈장과 비교하는 표준 분석에서 총 인자 Ⅷ 단백질 mg당 혈액응고 활성을 단위(unit)로 표시된다. 인자 Ⅷ의 활성 1 단위(unit)는 사람의 정상 혈장의 1 ml에서 존재하는 활성이다. 이러한 분석에서, 혈액응고에 걸리는 시간이 단축될수록 인자 Ⅷ의 활성은 증가한다. 돼지 인자 Ⅷ은 인간 인자 Ⅷ 분석시 응집활성을 갖는다.
"발현(expression)"은 유전정보가 하나의 산물을 생산하기 위해서 사용될 때 일어나는 일련의 과정을 의미한다. 돼지 인자 Ⅷ의 아미노산 서열을 인코딩하는 DNA는 돼지 인자 Ⅷ 단백질을 생산하기 위해서 숙주세포로써 포유세포에서 발현될 수 있다. DNA 서열의 발현을 유도할 수 있는 물질, 유전적 구조, 숙주세포 및 조건은 본 발명이 속하는 분야에서 공지되어 있으며, 발현에 걸리는 시간 및 발현양 뿐만 아니라 발현된 단백질의 세포내 세포외 위치도 조절할 수 있다. 예를 들면, 신호 펩타이드(signal peptide)를 인코딩하는 DNA를 돼지 인자 Ⅷ를 인코딩하는 DNA의 5' 말단(단백질의 NH2 말단을 인코딩하는 부분)에 도입함으로써, 발현된 단백질이 숙주세포 내에서 배양배지로 분비된다. 돼지 인자 Ⅷ를 인코딩하는 DNA에 신호 펩타이드(signal peptide)를 인코딩하는 DNA를 도입하는 것은 발현된 인자 Ⅷ가 배양배지로 분비되어 정제과정을 단순화시키는 이점이 있다. 신호 펩타이드는 포유세포 인자 Ⅷ 신호 펩타이드(mammalian factor Ⅷ signal peptide)인 것이 바람직하다.
인간 인자 Ⅷ cDNA 핵산 및 이의 예측되는 아미노산 서열은 서열번호 1과 2에 각각 명시되어 있다. 인자 Ⅷ은 "도메인(domain)" 서열 NH2-A1-A2-B-A3-C1-C2-COOH로 정의된 내부 서열 상동성(internal sequence homology)을 가진 약 300 kDa의 단일쇄 단백질로서 합성된다. 본 발명에서 사용된 인자 Ⅷ에 있는 "도메인(domain)"은 내부 아미노산 서열의 일치 및 트롬빈에 의해서 절단되는 부위에 의해서 정의된 연속된 아미노산 서열이다. 인간 인자 Ⅷ의 아미노산 서열(서열번호: 2)과 상동성 조사를 통해서 비교했을 때, 다른 특이사항이 없으면 인자 Ⅷ 도메인은 다음의 아미노산 서열을 포함한다: Ala1-Arg372 잔기로 구성된 A1; Ser373-Arg740 잔기로 구성된 A2; Ser741-Arg1648 잔기로 구성된 B; Ser1690-Ile2032 잔기로 구성된 A3; Arg2033-Asn2172 잔기로 구성된 C1; 및 Ser2173-Tyr2332 잔기로 구성된 C2. A3-C1-C2 서열은 Ser1690-Tyr2332의 잔기를 포함한다. 남은 부분, 즉 Glu1649-Arg1689 잔기는 일반적으로 인자 Ⅷ 경사슬 활성화 펩타이드(factor Ⅷ light chain activation peptide)로 언급된다. 인자 Ⅷ은 트롬빈 또는 인자 Ⅹa에 의한 단백질가수분해 작용에 의해서 활성화되는 데, 이때 폰 빌레브란트 인자(von Willebrand factor, vWF)로부터 해리되어 전혈액응고(procoagulant) 활성이 있는 인자 Ⅷa을 형성한다. 인자 Ⅷa의 생물학적 기능은 인자 Ⅹ를 활성화시키는 반응단계에서 인자 Ⅸa의 촉매효율을 증가시키는 것이다. 트롬빈에 의해서 활성화된 인자 Ⅷa은 혈소판 또는 단핵구(monocytes)의 표면에서 인자 Ⅸa와 인자 Ⅹ와 복합체를 형성하여 160 kDa의 분자량을 갖는 A1/A2/A3-C1-C2 이종삼중체(heterotrimer)이다. 본 발명에서 사용된 "부분적 도메인(partial domain)"은 하나의 도메인의 일부분을 형성하는 아미노산의 연속적인 서열을 의미한다.
본 발명에서 사용된 인간 또는 동물 인자 Ⅷ의 "서브단위(subunits)"는 단백질의 중사슬(heavy chains)과 경사슬(light chains)이다. 인자 Ⅷ의 중사슬은 A1, A2, B의 세 개의 도메인을 포함한다. 인자 Ⅷ의 경사슬은 A3, C1, C2 도메인을 포함한다.
본 발명에서 사용된 "에피토프(epitope)", "항원성 부위(antigenic site)", "항원성 결정인자(antigenic determinant)"은 동일한 의미로 사용되고, 항체에 의해서 특이적으로 인식되는 인간 또는 동물 인자 Ⅷ 또는 이들의 단편의 일부분을 의미한다.
본 발명에서 사용된 "면역원성 부위(immunogenic site)"는 인간 또는 동물에서 인자 Ⅷ 또는 이의 단편에 대해 특이적인 항체를 생성하도록 유도할 수 있는 인간 또는 동물 인자 Ⅷ 또는 이들 단편의 일부분을 의미하고, 이러한 항체생성은 면역학적 분석법(immunoassay), 예를 들면 ELISA, 또는 본 발명에서 사용한 베테스다 분석방법(Bethesda assay)과 같은 통상의 분석방법을 이용하여 측정될 수 있다. "면역원성 부위(immunogenic site)"는 몇 개 또는 다수개의 아미노산 잔기로 구성될 수 있고, 단백질의 1차, 2차, 또는 3차 구조에 의해서 결정된다. 본 발명의 실시예들에서, 혼성 또는 혼성에 상당하는(hybrid equivalent) 인자 Ⅷ 또는 이의 단편은 동물 또는 인간에서 비면역원성이거나 인간 또는 돼지 인자 Ⅷ보다 면역원성이 낮다.
본 발명에서 사용된 "인자 Ⅷ 결핍(factor Ⅷ deficiency)"은 혈액응고 활성에 있어서 결함을 포함하고, 이는 결함이 있는 인자 Ⅷ가 생성됨으로써, 인자 Ⅷ가 불충분하게 생성 또는 전혀 생성되지 않음으로써, 또는 인자 Ⅷ가 억제인자(inhibitors)에 의해서 부분적 또는 완전히 저해됨으로써 유발될 수 있다. 혈우병 A는 인자 Ⅷ이 결핍되어 나타나는 혈우병의 한 형태로서, X-연관 유전자에 결함이 있어서 이 유전자가 인코딩하는 인자 Ⅷ 단백질이 생성되지 않거나 결핍되어 나타나는 질환이다.
본 발명에서 사용된 "진단 분석방법(diagnostic assay)"은 항원-항체 반응을 의학적 치료방법을 선택하는 데 도움을 주는 테스트 샘플에 존재하는 특정 항체를 검출하고 정량화하는 데 이용하는 분석방법을 포함한다. 이러한 분석방법은 본 발명이 속하는 분야에서 통상의 지식을 가진 자에게 잘 알려져 있다. 본 발명에서 사용된 인간 또는 돼지 인자 Ⅷ DNA 또는 변형된 돼지 Ⅷ DNA, 또는 이들의 단편 및 이들 DNA에서 발현된 단백질의 전체 또는 일부분은 그 외 알려진 분석방법에서 사용된 이에 상응하는 시약대신에 사용될 수 있으며, 따라서 이러한 변형된 분석방법을 이용하여 인자 Ⅷ에 대한 항체를 검출하고 정량화할 수 있다. 이러한 시약, 즉 인자 Ⅷ DNA 또는 이의 단편 및 이들 DNA에서 발현된 단백질을 이용하여 종래에 알려진 분석방법을 변형시킴으로써 인간 또는 동물 인자 Ⅷ에 대한 항체를 검출할 수 있다. 이러한 분석방법은 ELISA, 면역확산 분석법(immunodiffusion assay), 면역탁본법(immunoblot)을 포함하고, 그러나 이에 한정되는 것은 아니다. 이러한 분석법을 실시하기 위한 방법은 본 발명이 속하는 분야에서 통상의 지식을 가진 자에게 잘 알려져 있다. 본 발명에서 사용된 적어도 하나의 에피토프(epitope)을 포함하는 인자 Ⅷ 또는 이의 단편은 진단 시약으로 사용될 수 있다. 인간, 돼지 또는 변형된 돼지 인자 Ⅷ 또는 이의 단편을 사용할 수 있는 다른 분석법의 예로는 베테스다 분석법(Bethesda assay)과 항응고 분석법(anticoagulation assay)을 포함한다.
"돼지 인자 Ⅷ와 같은 단백질을 인코딩하는 DNA"는 폴리디옥시 핵산(polydeoxynucleic acid)을 의미하며 이의 뉴클레오타이드(nucleotide) 서열은 알려진 유전암호(genetic code)에 따라서 단백질, 예를 들면 돼지 인자 Ⅷ의 아미노산 서열에 대한 코딩 정보를 나타낸다.
본 발명에서 사용된 인간 또는 동물 인자 Ⅷ 또는 변형된 인자 Ⅷ을 인코딩하는 DNA의 "발현 산물(expression product)"은 적당한 숙주세포에서 참조된 DNA의 발현을 통해서 수득되는 산물이고, 참조된 DNA에 인코딩된 단백질의 번역전 또는 번역후 변형된 특징을 포함하고, 이러한 변형으로는 당질화(glycosylation), 단백질 가수분해에 의한 절단(proteolytic cleavage) 등을 포함하고, 그러나 이에 한정되는 것은 아니다. 이러한 변형은 일어날 수 있고 숙주세포의 유형(type) 및 그 외 다른 요소에 따라서 다소 다르게 이루어 질 수 있으며, 전혈액응고(procoagulant) 활성을 가진 여러 형태의 분자적 이형체(isoforms)가 생성될 수 있다 (참고, Lind, P. et al., Eur. J. Biochem. 232:1927 (1995)).
"발현 벡터(expression vector)"는 DNA 성분으로서 일반적으로 원형구조로 되어 있고, 목적하는 숙주세포에서 자발적으로 복제할 수 있는 능력이 있거나 숙주세포의 게놈 내로 삽입(integration)할 수 있는 능력을 가지고 있으며, 또한 벡터 내로 적당한 위치에 적절한 방향으로 삽입된 코딩 DNA(coding DNA)의 발현을 유도할 수 있는 잘 알려진 조절인자를 가지고 있다. 이러한 조절인자는 이에 한정되는 것은 아니나 코딩 DNA의 전사를 개시할 수 있는 한 개 이상의 프로모터 서열, 인핸서(enhancer)과 같은 그 외 DNA 요소(element), 폴리아데닐레이션 부위(polyadenylation site) 및 그 외 본 발명에서 잘 알려진 조절인자를 포함한다. "발현 벡터"는 코딩하는 DNA가 벡터의 서열내로 발현 가능하도록 삽입되어 있는 벡터 및 삽입부위(insertion site)를 고려하면서 배열된 발현조절에 필수적인 요소를 가진 벡터 모두를 나타내고, 여기서 발현조절에 필수적인 요소는 삽입부위에 삽입된 코딩 DNA을 발현시키는 역할을 수행한다. 예를 들면, 프로모터를 가지고 있지 않은 벡터는 프로모터와 결합된 코딩 DNA을 도입함으로써 발현벡터가 될 수 있다.
본 발명에서 사용된 방법에 관한 설명
미국특허 제 5,364,771호는 혈액응고활성이 있는 혼성 인간/돼지 인자 Ⅷ 분자를 기재하고 있으며, 여기서 인간 또는 돼지 인자 Ⅷ 분자 내에 있는 요소(elements)는 다른 종에서 유래한 인자 Ⅷ 분자에 있는 이에 대응하는(corresponding) 요소로 치환되어 있다. 미국특허 제 5,663,060호는 혼성 인간/동물 및 혼성에 상당하는(hybrid equivalent) 인자 Ⅷ 분자에 대해서 기술하고 있고, 여기서 한 종에서 유래한 인자 Ⅷ 분자에 있는 요소(elements)는 다른 종에서 유래한 인자 Ⅷ 분자에 있는 이에 대응하는 요소(elements)로 치환되어 있다.
현재 B 도메인이 저해작용을 하는 에피토프를 가지고 있지 않고 인자 Ⅷ의 기능에 어떤 작용을 하는 지에 대해서 알려진 바가 없기 때문에, 본 발명의 실시예들에서 본 발명에서 설명한 방법을 이용하여 B 도메인이 혼성 또는 혼성에 상당하는 인자 Ⅷ 분자 또는 이의 단편에서 완전히 또는 부분적으로 소실된 인자 Ⅷ("B(-) factor Ⅷ)를 제조한다.
인간 인자 Ⅷ(human factor Ⅷ) 유전자는 다음의 참고문헌에 기술된 바와 같이 포유세포에서 분리하여 발현시켰고: Toole, J. J., et al., 312 Nature 342-347 (1984) (Genetics Institute); Gitschier, J., et al., 312 Nature 326-330 (1984) (Genentech); Wood, W. I., et al., 312 Nature 330-337 (1984) (Genentech); Vehar, G. A., et al., 312 Nature 337-342 (1984) (Genentech); WO 87/04187; WO 88/08035; WO 88/03558; U.S. Pat. No. 4,757,006, 아미노산 서열은 cDNA로부터 추정된 것이다. 카폰(Capon) 등에게 부여된 미국특허 제 4,965,199은 포유세포에서 인자 Ⅷ을 생산하는 재조합 DNA 방법 및 인간 인자 Ⅷ의 정제에 대해서 기술하고 있다. 인간 인자 Ⅷ가 CHO(Chinese hamster ovary) 세포, BHKC(baby hamster kidney cells)에서 발현된다는 것이 보고되고 있다. B 도메인이 완전히 또는 부분적으로 소실된 변형된 인간 인자 Ⅷ가 미국특허 제 4,868,112호에 기재되어 있고, 미국특허 제 5,004,803호에 기재된 바와 같이 B 도메인이 인간 인자 Ⅴ(human factor Ⅴ)의 B 도메인으로 치환된 변형된 인간 인자 Ⅷ의 제조가 시도되었다. 인간 인자 Ⅷ을 인코딩하는 cDNA 서열 및 이의 예측된 아미노산 서열은 서열번호 1 및 2에 각각 나타낸 바와 같다. 서열번호 1에서 코딩 부위(coding region)는 뉴클레오타이드 208 위치에서 시작하고, 여기서 GCC 트리플렛 코드(triplet code)는 서열번호 2에 나타낸 바와 같이 성숙된 단백질의 1번 아미노산 (Ala)을 지정한다.
돼지 인자 Ⅷ는 혈장에서 분리된 것이다 (Fass, D. N., et al., 59 Blood 594 (1982)). 돼지 인자 Ⅷ의 아미노산 서열중 일부는 세룰로플라스민(ceruloplasmin)과 혈액응고인자 Ⅴ에 상동성이 있는 N-말단 경사슬(light chain) 서열의 일부와 대응한다(corresponding to) (Church et al., 81 Proc. Natl. Acad. Sci. USA 6934 (1984)). 돼지 인자 Ⅷ의 4개의 아미노산 단편의 N-말단의 서열은 부분적으로 결정되었으나 (Toole, J. J., et al., 312 Nature 342-347 (1984)), 이러한 단편이 돼지 인자 Ⅷ의 어느 위치에 존재하는 지에 대해서는 규명이 되지 않고 있다. B 도메인의 아미노산 서열과 A2 도메인의 일부 아미노산 서열이 결정되었다 (Toole, J. J., et al., 83 Proc. Natl. Acad. Sci. U.S.A. 5939-5942 (1986)). 미국특허 제 5,364,771호는 돼지 인자 Ⅷ의 완전한 A2 도메인의 cDNA 서열, 이의 예측된 아미노산 서열, 및 모든 도메인, 모든 서브단위(subunits) 및 특정 아미노산 서열이 치환된 혼성 인간/돼지 인자 Ⅷ에 대해서 기재하고 있다. 상기 미국특허 제 5,364,771호는 혼성 인간/돼지 인자 Ⅷ(hybrid human/porcine factor Ⅷ)을 발명의 명칭으로 하여 1994년 11월 15일자로 특허권을 부여받았고, 1993년 10월 14일자로 국제특허 제 WO 93/20093호로 공개되었다. 서열번호 1에 기재된 바와 같이 성숙된 인간 인자 Ⅷ(mature human factor Ⅷ)의 373 내지 740의 아미노산 잔기에 대응하는(corresponding to) 돼지 인자 Ⅷ의 A2 도메인을 인코딩하는 cDNA 서열 및 이의 예측된 아미노산 서열은 각각 서열번호 3과 4에 명시된 바와 같다. 1994년 5월 26일자로 공개된 국제특허 제 WO 94/11503호는 돼지 인자 Ⅷ의 198번 아미노산이 소실된 A1 도메인과 A2 도메인의 핵산 서열 및 이에 상응하는 아미노산 서열을 기재하고 있다. 완전한 A1 도메인, 활성화 펩타이드(activation peptide), A3 도메인, C1 도메인, C2 도메인뿐만 아니라 인코딩된 아미노산 서열을 포함해서, 돼지 인자 Ⅷ을 인코딩하는 전체 뉴클레오타이드 서열의 획득은 롤라(Lollar)에 의해서 이루어졌고, 이는 1999년 1월 12일자로 투여권을 부여받은 미국특허 제 5,859,204호 및 1997년 12월 31일자로 공개된 국제특허 제 WO 97/49725호에 기재되어 있고, 이 두 특허는 본 발명에서 명시한 참고문헌에 수록되어 있다.
돼지 및 인간 인자 Ⅷ은 모두 두 개의 서브단위(subunit)으로 구성된 단백질로서 혈장에서 분리된 것이다. 상기 두 개의 서브단위는 중사슬(heavy chain)과 경사슬(light chain)로써 칼슘 또는 다른 이가 금속이온의 매개에 의해서 비공유적으로 서로 결합되어 있다. 인자 Ⅷ의 중사슬은 A1, A2, B 도메인을 포함하고 있으며, 이들 세 개의 도메인은 서로 공유적으로 연결되어 있다. 또한, 인자 Ⅷ의 경사슬은 A3, C1, C2 도메인을 포함한다. B 도메인의 경우, 아직까지 생물학적 기능이 밝혀져 있지 않으며, 인자 Ⅷ 분자의 측정가능한 매개변수에 크게 영향을 주지 않으면서 이 분자로부터 단백질 가수분해에 의해서 또는 재조합 DNA 기술을 이용하여 부분적으로 또는 완전히 제거될 수 있다. 재조합된 인간 인자 Ⅷ(human recombinat factor Ⅷ)은 포유세포에서 발현되지 않아서 당질화가 되어 있지 않을 경우에도 혈장유래인자 Ⅷ과 유사한 구조 및 기능을 갖는다.
활성화된 인간 및 돼지 인자 Ⅷ (factor Ⅷa)은 모두 A1과 A2 도메인 사이에 있는 중사슬의 절단으로 인해서 세 개의 서브단위(subunit)를 가지고, 이러한 구조는 A1/A2/A3-C1-C2로 나타낸다. 인간 인자 Ⅷa는 돼지 인자 Ⅷa를 안정화시키는 조건에서 불안정하고, 이는 인간 인자 Ⅷa에서는 A2 서브단위가 더 약하게 결합되어 있기 때문일 것으로 생각된다. 인간 및 돼지 인자 Ⅷa로부터 2 서브단위의 해리는 인자 Ⅷa의 활성이 소실을 초래할 수 있다 (Yakhyaev, A. et al. (1997) Blood 90:Suppl. 1, 요약서 #126, LDL(low density lipoprotein) 수용체-관련 단백질이 A2 도메인에 결합하면 A2 도메인은 세포내로 유입되기 때문에 인자 Ⅷ의 활성을 저하시킨다)
"B 도메인이 소실된 인자 Ⅷ(B-domainless factor Ⅷ)"의 발현은 B 도메인의 일부분을 도입시킴으로써 증가될 수 있다. "SQ" (Lind, P. et al. (1995) supra)로서 표시되는 B 도메인의 일부분을 도입함으로써 발현이 증가된다고 보고되었다. "SQ" 구성물(construct)은 B 도메인의 N-말단에 있는 5개의 아미노산과 C-말단에 있는 9개의 아미노산을 제외한 나머지 부분을 포함하고 있지 않다.
정제된 혼성 인자 Ⅷ 또는 이의 단편의 면역반응성 및 혈액응고 활성은 정제된 재조합 인간 인자 Ⅷ을 표준물질로 사용하여 혈장이 없는 조건에서 인자 Ⅷ의 분석법(plasma-free factor Ⅷ assay), 일단계 혈액응고 분석법(one-step clotting assay), ELISA(enzyme-linked immunosorbent assay)와 같은 표준 분석법을 통해서 분석될 수 있다.
플라스미드 및 포유세포용 바이러스 벡터를 포함해서 그 외 벡터는 본 발명이 속하는 분야의 기술을 습득한 자의 선호도와 판단에 따라서 포유 세포에서 재조합 유전자 구조물(construct)의 발현에 사용될 수 있다 (참고, 예를 들면, Sambrook et al., Chapter 16). 다른 벡터와 박테리아, 효모, 곤충 세포에서의 발현 시스템이 사용될 수 있고, 그러나 당질화(glycosylation)에서 차이가 나거나 당질화가 이루어지지 않기 때문에 바람직하지는 않다.
재조합 인자 Ⅷ 단백질은 세포 배양 및 재조합 단백질의 포유세포에서의 발현을 목적으로 통상적으로 사용하는 다양한 세포에서 발현될 수 있다. 특히, 다수의 설치류에서 유래한 세포주(cell lines)는 분자량이 큰 단백질의 발현에 유용한 숙주세포로서 알려져 있다. 이러한 세포주는 미국세포주은행(American Type Culture Collection, Rockville, MD)에서 구매가능하며, 바람직한 세포주로는 BHKC(baby hamster kidney cells)과 CHO 세포(chinese hamster ovary cells)을 포함하며, 이들 세포주는 일반적인 배양방법과 배지를 이용하여 배양된다.
돼지 A2 서브단위가 돼지 인자 Ⅷa로부터 자발적으로 해리되는 속도보다 인간 A2 서브단위(subunit)가 인간 인자 Ⅷa로부터 더 빠르게 해리되기 때문에, 돼지 인자 Ⅷ의 혈액응고 활성은 인간 인자 Ⅷ보다 훨씬 더 크게 나타난다. 인자 Ⅷa에서 A2 서브단위가 해리되면 혈액응고 활성을 잃게 된다 (Lollar, P. et al. (1990) J. Biol. Chem. 265:1688-1692; Lollar, P. et al. (1992) J. Biol. Chem. 267:23652-23657; Fay, P. J. et al., (1992) J. Biol. Chem. 267:13246-13250).
면역 반응성이 감소된 인자 Ⅷ 분자
인자 Ⅷ의 혈액응고 활성을 억제하는 항체("억제인자(inhibitor)" 또는 "억제성 항체(inhibitory antibody)")와 면역반응성이 있는 에피토프(epitope)는 인자 Ⅷ의 구조와 기능사이의 알려져 있는 관계를 토대로 결정된 것이다. 억제인자는 인자 Ⅷ의 도메인 구조와 거대분자와의 상호작용 또는 폰 빌레브란트 인자(von Willebrand factor, vWF), 트롬빈, 인자 Ⅹa, 인자 Ⅸa 또는 인자 Ⅹ와 거대분자와의 상호작용을 파괴함으로써 억제작용을 나타낼 것으로 추측된다. 그러나, 대부분의 인간 인자 Ⅷ에 대한 억제성 항체(inhibitory antibody)는 40kDa의 A2 도메인 또는 20 kDa의 C2 도메인에 위치한 에피토프에 결합하여 이러한 도메인의 기능을 저해함으로써 억제작용을 나타낸 (Fulcher et al., (1995) Proc. Natl. Acad. Sci. USA 82:7728-7732; sCANDELLA ET AL. (1988) Proc. Natl. Acad. Sci. USA 85:6152-6156). A2와 C2 도메인에 있는 에피토프 이외에 경사슬(light chain)의 A3 또는 C1 도메인에 세 번째 에피토프의 존재 가능성이 보고된 바 있다 (Scandella et al. (1993) Blood 82:1767-1775). 이러한 세 번째 에피토프의 중요성에 대해서 알려진 바는 없지만, 인자 Ⅷ에서 세 번째 에피토프의 반응성은 크게 중요하지 않는 것 같다.
A2에 대한 항체(anti-A2 antibodies)는 인자 Ⅹ의 활성화 단계를 저해한다 (Lollar et al. (1994) J. Clin. Invest. 93:2497-2504). 소실 돌연변이 (deletion mutagenesis) 유발을 통해서 맵핑(mapping)한 결과, A2 에피토프는 40 kDa A2 도메인의 N-말단의 20 kDa 영역에 위치한다는 것이 밝혀졌다 (Ware et al. (1992) Blood Coagul. Fibrinolysis 3:703-716). 경쟁적 면역방사계수측정(competition immunoradiometric assay)을 통해서 A2 억제인자는 한 개의 에피토프 또는 공간상 아주 근접하여 존재하는 에피토프들을 인식한다는 것이 알려졌다 (Scandella et al. (1992) Throm. Harmostas 67:665-671; 미국특허 제 5,859,204호).
동물 또는 변형된 동물 인자 Ⅷ 분자의 항원성(antigenicity) 및/또는 면역원성(immunogenicity)은 임상적 시도로서 사람에서 검사될 수 있다. 인자 Ⅷ가 억제성 항체(inhibitory antibody)와 면역반응성이 있는지를 결정하고자 하는 경우, 인자 Ⅷ는 치료목적의 인간 인자 Ⅷ의 혈액응고 활성을 억제할 수 있는 항체를 가진 인자 Ⅷ 결핍성 환자 약 25명에게 투여되고, 이때 정맥내로 투여하는 것이 바람직하다. 동물 또는 변형된 동물 인자 Ⅷ 분자의 용량(dosage)은 5-50 단위/kg 몸무게, 바람직하게는 10-50 단위/kg 뭄무게, 가장 바람직하게는 40 단위/kg 몸무게. 각 투여후 약 1시간 후, 혈액 샘플에서 인자 Ⅷ를 회수하여 일단계 혈액응고 분석법(one-stage coagulation assay)을 이용하여 분석한다. 투여한지 약 5시간 후에 다시 혈액샘플을 받아서 회수된 인자 Ⅷ의 양을 측정한다. 샘플에서 인자 Ⅷ의 총 회수량과 사라지는 속도는 항체 역가와 항체의 억제활성을 나타낸다. 항체 역가가 아주 높다면 회수시 인자 Ⅷ는 일반적으로 측정되지 않는다. 이러한 회수 결과는 인간 혈장유래인자 Ⅷ, 재조합 인간 인자 Ⅷ, 돼지 혈장유래인자 Ⅷ, 그 외 통상적으로 사용되는 인자 Ⅷ 또는 인자 Ⅷ의 대용물질의 치료용 제형으로 치료받은 환자에서의 회수결과와 비교된다.
임상적으로 중요하게 작용하는 에피토프를 결정한 후, 억제인자를 함유하는 혈장의 광범위한 in vitro 조사를 통해서 돼지 혈장유래인자 Ⅷ보다 낮거나 비슷한 교차반응성(cross-activity)을 가지는 재조합 인자 Ⅷ 분자를 제조하여 발현시킬 수 있다. 또한, 에피토프 영역에서 교차반응성을 저하시킬 수 있는 돌연변이가 추가로 이루어질 수 있다. 교차반응성(cross-reactivity)의 감소는 바람직함에도 불구하고 돼지에서 유래한 단백질 또는 바이러스 또는 프리온(prion)과 같은 감염성이 있는 오염물질을 함유하고 있기 때문에 부작용을 유발할 수 있는 돼지 혈장유래인자 Ⅷ의 농축액에 비해서 장점이 있는 산물을 생성하는 데는 필요하지 않다. 돼지 재조합 또는 변형된 Ⅷ 분자는 돼지에서 유래한 외래 단백질을 포함하지 않는다.
진단 분석법(diagnostic assay)
인자 Ⅷ cDNA 및/또는 이로부터 발현된 단백질의 전체 또는 일부분은 이간 또는 동물 인자 Ⅷ 또는 변형된 동물 인자 Ⅷ에 대한 억제성 항체(inhibitory antibody)를 기질(substrate)에서 검출하기 위한 분석에서 진단시약으로 사용될 수 있다. 상기 기질의 예는 인자 Ⅷ 결핍증 환자의 혈청 및 체액 샘플을 포함한다. 이러한 항체 분석법은 ELISA, 면역탁본법(immunoblot), 방사선면역 분석법(radioimmunoassay), 면역확산 분석법(immunodiffusion assay), 인자 Ⅷ의 생물학적 활성을 측정할 수 있는 분석법 (예, 혈액응고 분석법(coagulation assay)) 등을 포함한다. 이러한 진단시약의 제조기술 및 이의 사용 방법은 본 발명이 속하는 분야에서 통상의 지식을 가진 자에게 잘 알려져 있다. 예를 들면, 환자의 혈청 샘플에서 억제성 항체를 검출할 수 있는 면역분석법(immunoassay)은 테스트 샘플을 충분한 양의 인자 Ⅷ와 반응시키는 단계를 포함할 수 있고, 이때 항원성 인자 Ⅷ를 포함하는 테스트 샘플내에서 인자 Ⅷ는 억제성 항체와 검출가능한 복합체를 형성한다.
핵산 및 아미노산 프로브는 혼성 인자 Ⅷ cDNA 또는 단백질 분자, 또는 이들의 단편의 서열에 기초하여 제조될 수 있다. 본 발명의 실시예들에서, 이러한 프로브는 염색시약(dye) 또는 효소반응, 형광, 화학chemiluminescent 또는 방사선을 이용하여 라벨링될 수 있고, 이들 라벨링 시약 및 화합물은 구매 가능하다. 예를 들면, 아미노산 프로브는 인간, 동물 또는 혼성 인간/돼지 인자 Ⅷ가 존재할 것으로 의심되는 혈청 또는 그 외 체액을 스크리닝하는 데 사용될 수 있다. 환자에서 측정된 억제인자의 농도는 정량화하여 건강한 사람의 것을 대조구(control)로 사용한 경우와 비교분석하는 데 이용될 수 있고, 예를 들면, 인자 Ⅷ 결핍증 환자가 동물 또는 변형된 동물 인자 Ⅷ로 치료받을 수 있는 지의 여부를 판단하는 데 이용될 수 있다. cDNA 프로브는 예를 들면 DNA 라이브러리(library)를 스크리닝하는 연구에 사용될 수 있다.
약제학적 조성물
재조합 돼지 또는 변형된 돼지 인자 Ⅷ을 함유하는 약제학적 조성물은 마틴(E. W. Martin)이 저술한 레밍톤의(Remington's) Pharmaceutical Sciences에 기재된 바와 같은 공지의 방법에 따라서 단독으로 또는 약제학적 안정화제, 전달 매체(delivery vehicles) 및/또는 담체 운반체(vehicles)와 조합으로 제조된다.
본 발명의 바람직한 일실시예에서, 정맥투여시 바람직한 담체 운반체 또는 전달 매체는 생리식염수 또는 인산완충용액이다.
본 발명의 바람직한 일실시예에서, 적당한 안정화제, 전달 매체, 담체 운반체는 이에 한정하는 것은 아니나 알부민과 같은 인간 또는 동물 단백질을 포함한다.
또한, 인지질 vesicle 또는 리포좀(liposome) 현탁액은 약제학적으로 허용되는담체 운반체 또는 전달 매체로서 바람직하고, 본 발명이 속하는 분야에서 통상의 지식을 가진 자에게 공지되어 있는 방법에 따라서 제조될 수 있으며, 예를 들면, 인자 Ⅷ은 음전하를 띤 인지질 막에 결합하기 때문에, 표면에 음전하를 부여할 수 있는 포스파티딜세린/포스파티딜콜린(phosphatidylserine/phosphatidylcholine) 또는 그 외 인지질 또는 계면활성제(detergent) 성분을 포함할 수 있고, 이들은 , 리포좀은 적당한 지질(들)(예를 들면, 스테아로일 포스파티딜 에탄올아민 (stearoyl phosphatidyl ethanolamine), 스테아로일 포스파티딜 콜린 (stearoyl phosphatidyl choline), 아라카도일 포스파티딜 콜린 (arachadoyl phosphatidyl choline), 콜레스테롤)을 무기 용매에 용해시킨 후 용매를 휘발시켜 제거하여 용기의 표면에 건조되어 얇은 막을 형성한 지질 형태로 제조될 수 있다. 혼성 인자 Ⅷ (hybrid factor Ⅷ)을 함유하는 수용액을 상기 용기에 첨가한 후, 용기를 손으로 돌리면서 free lipid 물질을 용기의 표면으로부터 자유롭게 하여 뭉쳐있는 지질을 분산시킴으로써 리포좀 현탁액이 형성된다.
재조합 돼지 또는 변형된 돼지 인자 Ⅷ은 다른 적당한 안정화제, 전달 매체 및/또는 담체 운반체와 조합으로 사용될 수 있고, 이들의 예는 비타민 K 의존성 혈액응고 인자, 조직 인자(tissue factor), 폰 빌레브란트 인자(von Willebrand factor, vWf) 또는 인자 Ⅷ에 대한 결합부위를 함유하는 vWf의 단편, 및 수크로스(sucrose)와 같은 탄수화물을 포함한다.
또한, 재조합 돼지 또는 변형된 돼지 인자 Ⅷ은 인간 인자 Ⅷ을 전달할 수 있는 유전자 치료와 같은 방법을 통해서 레트로바이러스(retrovirus) 벡터와 같은 전달 수단을 이용하여 전달될 수 있다. 이러한 전달은 목적하는 인자 Ⅷ 구조물(construst) cDNA을 인자 Ⅷ 결핍증 환자에게 직접 이식된 인간 세포내로 도입하거나 인자 Ⅷ 분자에 대해서 투과성이 있으나 세포에 대한 투과성은 없는 이식 가능한 장치에 있는 인간 세포내로 도입하여 이식하는 방법을 이용하여 달성된다. 바람직한 방법은 레트로바이러스(retrovirus)의 매개에 의해서 유전자를 전달하는 것이다. 이러한 방법에서, 외래 유전자(예, 인자 Ⅷ cDNA)는 변형된 레트로바이러스의 게놈내로 클로닝된 후 바이러스의 기구(machinery)에 의해서 숙주세포의 게놈내로 삽입되고 세포의 발현시스템에 의해서 발현된다. 여기서 레트로바이러스 벡터를 바이러스를 생산하지 못하는 형태로 변형함으로써, 숙주세포가 바이러스에 감염되는 것을 방지한다. 이와 같은 유전자 치료방법은 본 발명이 속하는 분야에서 통상의 지식을 가진 자에게 공지되어 있고, 다음 문헌에 리뷰(review)되어 있다: Kohn, D.B. et al. (1989) Transfusion 29:812-820.
돼지 또는 변형된 돼지 인자 Ⅷ은 혼성 분자의 반감기 및 저장기간(shelf-life)을 증가시키기 위하여 vWf에 결합된 형태로 저장될 수 있다. 또한, 인자 Ⅷ을 동결건조함으로써 vWf의 존재시 활성 분자의 효율은 향상시킬 수 있다. 현재 상업적으로 제공되는 인간 및 동물 인자 Ⅷ을 저장하는 방법을 이용하여 재조합 인자 Ⅷ을 저장할 수 있다. 이러한 방법으로는 (1) 부분적으로 정제된 상태의 인자 Ⅷ (예, 더 이상의 정제되지 않고 주입되는 인자 Ⅷ 농축물)의 동결건조; (2) 지머만 방법(Zimmerman method)을 이용하여 면역친화도(immunoaffinity)에 의한 인자 Ⅷ의 정제 및 인자 Ⅷ을 안정화 시키는 알부민 존재하에서 동결건조; (3) 알부민 존재하에서 재조합 인자 Ⅷ의 동결건조 등을 포함한다.
또한, 돼지 또는 변형된 돼지 인자 Ⅷ은 0.6 M NaCl, 20 mM MES, 5 mM CaCl2을 포함하는 버퍼용액(pH 6.0)내에서 4℃에서 영원히 안정한 것으로 밝혀졌고, 또한 이러한 버퍼용액에서 동결된 상태로 저장될 수 있으며 인자 Ⅷ의 활성의 손실을 최소화하면서 해동될 수 있다.
치료방법
재조합 돼지 또는 변형된 돼지 인자 Ⅷ은 억제성 항체(inhibitory antibody)을 가지고 있거나 가지고 있지 않은 혈우병 환자 및 억제성 항체의 생성으로 인해서 유발된 인자 Ⅷ 결핍증 환자에서 인자 Ⅷ의 결핍으로 인한 조절이 되지 않는 출혈(예, 관절내 출혈, 두개강내 출혈, 위장내 출혈)을 치료하는 데 사용될 수 있다. 활성 물질은 정맥내로 투여하는 것이 바람직하다.
또한, 재조합 돼지 또는 변형된 돼지 인자 Ⅷ은 상기에 설명한 바와 같은 세포를 함유하는 장치의 이식을 통해서 단백질을 유전공학적인 방법으로 생산할 수 있는 세포를 이식하는 방법을 이용하여 투여될 수 있다.
본 발명의 바람직한 일실시예에서, 재조합 돼지 또는 변형된 돼지 인자 Ⅷ을 단독으로 또는 안정화제, 전달 매체 및/또는 담체와의 조합으로 포함하는 약제학적 조성물은 인간 또는 동물 인자 Ⅷ을 투여하는 경우와 동일한 방법으로 환자에게 정맥내로 투여된다.
재조합 돼지 또는 변형된 돼지 인자 Ⅷ을 필요로 하는 환자에게 투여시 용량(dosage)은 인자 Ⅷ 결핍증의 상태에 따라서 다르다. 일반적으로, 각 환자의 출혈이 지속된 시간 및 상태를 고려하면서 투여 횟수, 투여 기간, 투여 단위가 결정된다. 따라서, 인자 Ⅷ은 출혈을 멈추게 할 수 있는 치료상 유효한 양의 단백질이 환자에게 전달되기에 충분한 양으로 약제학적으로 허용되는 담체, 전달 매체, 또는 안정화제에 함유될 수 있고, 여기서 표준 혈액응고 분석법(standard clotting assay)을 이용하여 유효한 양을 측정할 수 있다.
인자 Ⅷ은 원래 정상적인 혈장에 존재하는 물질로서 정의되며, 혈우병 A 환자에서 유래한 혈장에서 혈액응고의 결함을 교정할 수 있다. 인자 Ⅷ의 정제된 형태 및 부분적으로 정제된 형태의 in vitro 혈액응고 활성은 환자에게 적용될 인자 Ⅷ의 투여량을 산출하는 데 이용되고, 환자의 혈장에서 혈액응고의 회복 및 in vivo 출혈 장애의 교정에 대한 지표로서 사용될 수 있다. 새로운 인자 Ⅷ 분자의 in vitro 표준 분석결과와 주입모델동물로서 개 또는 환자에서 상기 분자에 대한 분석결과사이에 별다른 차이점은 보고된 바 없다 (Lusher, J. M. et al. 328 New Engl. J. Med. 328:453-459; Pittman, D. D. et al. (1992) Blood 79:389-397; Brinkhous et al. (1985) Proc. Acad. Sci. 82:8752-8755).
일반적으로, 재조합 돼지 또는 변형된 돼지 인자 Ⅷ을 환자에게 투여할 경우, 혈장에서 인자 Ⅷ의 활성이 정상 혈장의 경우의 30-100 % 범위에 도달하면 바람직하다. 치료 인자 Ⅷ의 바람직한 투여형태에서, 조성물은 바람직하게는 5-50 단위/kg 몸무게 범위의 투여량으로, 더욱 바람직하게는 10-50 단위/kg 몸무게 범위의 투여량으로, 가장 바람직하게는 20-40 단위/kg 몸무게 범위의 투여량으로 정맥으로 투여되고, 8 내지 24 시간(증세가 심각한 혈우병환자의 경우)의 간격을 두고 투여되어야 하며, 치료기간은 1 내지 10일 동안 또는 출혈현상이 치료될 때까지 지속된다 (참고, 예, Roberts, H.R., 및 M.R. Jones, "Hemophilia and Realted Conditions-Congenital Deficiencies of Prothrombin (Factor Ⅱ, Factor Ⅴ, and Factors Ⅶ to ?)," Ch. 153, 1453-1474, 1460, in Hematology, Williams, W. J., et al., ed. (1990)). 억제인자를 가지고 있는 환자는 인자 Ⅷ의 원래 형태보다는 재조합 돼지 또는 변형된 돼지 인자 Ⅷ을 더욱 필요로 하고 이때 요구되는 양도 다르다. 예를 들면, 재조합 돼지 또는 변형된 돼지 인자 Ⅷ는 인간 인자 Ⅷ 보다 더 높은 비활성(specific activity)을 가지고 있고 항체에 대한 반응성이 낮기 때문에, 환자는 상대적으로 적은 양의 재조합 돼지 또는 변형된 돼지 인자 Ⅷ을 필요로 한다. 인간 또는 돼지 혈장유래인자 Ⅷ을 이용한 치료에 있어서, 치료 인자 Ⅷ의 투여량은 일단계 인자 Ⅷ 혈액응고 분석법을 이용하여 결정되고, 필요한 경우 in vivo 회복정도는 주입 후 환자의 혈장에서 인자 Ⅷ을 측정하여 결정한다. 여기서 투여량은 개개인의 요구 및 상기 조성물의 투여를 실시하거나 감독하는 사람의 전문적인 판단에 따라서 결정되어야 하고, 상기의 농도범위는 단지 예시적인 것이며 청구된 조합물의 범위 또는 적용을 한정적이 아닌 것으로서 이해되어야 한다.
치료는 본 발명의 조성물을 정맥내로 일회 투여하는 형태로 이루어질 수 있고, 또는 필요에 따라서 장기간 주기적으로 또는 연속해서 투여하는 형태로 이루어질 수 있다. 또한, 치료 인자 Ⅷ은 시간 간격을 다양하게 하면서 일회 또는 여러 번 피하 또는 리포좀(liposome) 형태로 경구 투여될 수 있다.
또한, 재조합 돼지 또는 변형된 돼지 인자 Ⅷ은 인간 인자 Ⅷ에 대한 항체가 생성된 혈우병 환자에서 인자 Ⅷ의 결핍으로 인해서 유발되는 조절되지 않는 출혈을 치료하는 데 사용될 수 있다. 이러한 경우, 혈액응고 활성이 인간 또는 동물 인자 Ⅷ보다 우수할 필요는 없다. 혈액응고 활성이 환자의 혈장에 있는 항체에 의해서 중화되지 않는다면, 인간 인자 Ⅷ보다 낮은 혈액응고 활성(즉, ＜3,000 units/mg)이 유용하다.
본 발명에서 증명된 바와 같이, 재조합 돼지 또는 변형된 돼지 인자 Ⅷ의 비활성(specific activity)은 인간 인자 Ⅷ와 다를 수 있다. 인간 인자 Ⅷ보다 높은 혈액응고 활성을 가지는 인자 Ⅷ 단백질은 상대적으로 적은 양으로도 환자의 인자 Ⅷ 결핍현상을 치료할 수 있기 때문에 혈우병 치료에 유용하다. 인간 인자 Ⅷ보다 상대적으로 낮은 혈액응고 활성을 가지는 인자 Ⅷ 단백질 또한 치료목적으로 사용될 수 있고 이때 정상적인 인간 인자 Ⅷ와 비교했을 때 단지 1 %의 비활성을 가지더라도 치료에 적용하기에 적당하다. 따라서, 본 발명의 혈액응고 활성을 가지는 인자 Ⅷ의 비활성(specific activity)은 인간 인자 Ⅷ의 적어도 1%에 해당한다.
상기에 설명한 본 발명에 따른 재조합 돼지 또는 변형된 돼지 인자 Ⅷ 분자 및 이의 분리, 특징결정, 제조, 이용 방법은 하기의 실시예로 보다 구체적으로 예시될 것이다. 그러나 이들 실시예가 단지 본 발명의 구현 예이며 본 발명의 범위를 한정하는 것은 아니다.
[실시예 1] 돼지 인자 Ⅷ과 혼성 인간/돼지 인자 Ⅷ에 대한 분석
돼지 인자 Ⅷ은 인간 인자 Ⅷ보다 높은 혈액응고 활성을 가지며, 이는 비활성(specific activity)을 바탕으로 한다. 여기서 인간 또는 돼지 인자 Ⅷ을 공정하게 비교할 수 있는 정확한 표준곡선을 사용하여 이러한 결론을 얻었다. 응집활성 분석은 인자 Ⅷ의 혈우병 A 환자에서 유래한 혈장의 혈액응고에 걸리는 시간(clotting time)을 단축시킬 수 있는 능력을 조사한 것이고, 일단계 분석법(one-stage assay) 및 이단계 분석법(two-stage assay)을 이용하여 수행하였다.
일단계 분석법에서, 혈우병 A 환자의 혈장 (George King Biomedical, Inc.) 0.1 ml을 활성화된 부분 트롬보플라스틴 시약(activated partial thromboplastin time(APTT) reagent, Organon Teknika) 0.1 ml과 샘플 또는 표준시료 0.01 ml과 함께 5분 동안 37 ℃에서 진탕배양하였고, 여기서 표준시료는 시트레이트(citrate)가 함유된 정상 사람혈장을 희석시킨 것을 사용하였다. 배양후 0.1 ml의 20 mM CaCl2을 첨가하고 피브린혈전의 생성을 육안으로 관찰하여 혈액응고 시간(clotting time)을 결정하였다.
인자 Ⅷ의 1 단위(unit)는 시트레이트(citrate)가 함유된 정상 사람혈장의 1 ml에 존재하는 양을 의미한다. 사람혈장을 표준시료로 사용하면서, 돼지 및 인간 인자 Ⅷ의 활성은 직접 비교되었다. 0.15 M NaCl와 0.02 M HEPES로 구성된 버퍼용액 (pH 7.4)을 이용하여 표준시료로 사용된 혈장 또는 정제한 단백질을 희석하였다. 표준곡선은 3 또는 4회 희석시킨 혈장을 사용하여 얻었고 이때 희석은 최고 50배까지 하였으며, 로그값(log10)의 혈액응고 시간(clotting time)을 로그값의 혈장 농도에 따라서 곡선으로 표시하였다. 샘플에서의 인자 Ⅷ의 단위(unit)는 표준곡선을 이용하여 산출되었다.
일단계 분석법에서 인자 Ⅷ은 혈우병 A 환자의 혈청에서 형성된 활성인자(activator)에 의해서 활성화되어 내인계응고가 일어난다. 반면, 이단계 분석법은 미리활성화된 인자 Ⅷ의 전혈액응고 활성(procoagulant activity)을 측정한다. 이단계 분석법에서, 트롬빈으로 처리된 인자 Ⅷ을 함유하는 샘플은 활성화된 트롬보플라스틴 단편(activated partial thromboplastin)와 혈우병 A 환자의 혈장으로 이루어진 혼합물에 첨가하였고, 여기서 혼합물은 미리 37 ℃에서 5분 동안 배양하여 사용하였다. 측정된 혈액응고 시간을 상기에서 설명한 것과 동일한 사람혈장을 이용한 표준곡선을 이용하여 단위(units)/ml로 전환하였다. 이단계 분석법에서 상대적 활성도는 일단계 분석법보다 높았고 이러한 결과는 인자 Ⅷ가 미리 활성화되어 있었기 때문이다.
[실시예 2] 인간 인자 Ⅷ와 돼지 인자 Ⅷ의 기능적 차이
돼지 및 인간 혈장유래인자 Ⅷ과 인간 재조합 인자 Ⅷ은 다음의 문헌에 기술된 방법에 따라서 분리하였다: Fulcher, C. A., et al. (1982) Proc. Natl. Acad. Sci. U.S.A. 79:1648-1652; Toole, J. J., et al., (1984) Nature 312:342-347 (Genetics Institute); Gitschier, J., et al., (1984) Nature 312:326-330 (Genentech); Wood, W. I., et al., (1984) Nature 312:330-337 (Genentech); Vehar, G. A., et al., (1984) Nature 312:337-342 (Genentech); Fass, D. N., et al., (1982) Blood 59:594 ; Toole, J. J., et al., (1986) Proc. Nat'l. Acad. Sci. U.S.A. 83:5939-5942. 이러한 분리는 몇가지 방법을 이용하여 수행될 수 있다. 인간 인자 Ⅷ와 돼지 인자 Ⅷ사이에 안정성 측면에서 기능적 차이는 있지만, 이러한 방법으로 분리된 인자 Ⅷ은 모두 서브단위(subunit)로 구성된 조성면에서 비슷하다.
인간 재조합 인자 Ⅷ와 돼지 인자 Ⅷ를 비교하는 경우, 인간 재조합 인자 Ⅷ (Cutter Laboratories, Berkeley, CA)와 돼지 인자 Ⅷ (immunopurified as described in Fass, D. N., et al. (1982) Blood 59:594)은 Mono QTM (Pharmacia-LKB, Piscataway, N.J.) 이온교환수지 (Pharmacia, Inc.)를 이용하여 HPLC (high-pressure liquid chromatography)을 수행하여 고순도로 분리정제하였다. Mono QTM HPLC을 수행하는 목적은 인간 및 돼지 인자 Ⅷ가 함유된 일반적인 버퍼용액에서 비교분석시 영향을 줄 수 있는 미량의 불순물을 제거하기 위함이다. 인자 Ⅷ의 1000-2000 단위(unit)를 함유하는 바이알에 5 ml의 물을 넣은 후, Hepes 버퍼용액 (2M, pH 7.4)을 최종농도가 0.02 M이 되도록 첨가한다. 인자 Ⅷ은 0.15 M NaCl, 0.02 M Hepes, 5 mM CaCl2을 함유하는 버퍼용액(pH 7.4, 버퍼 A + 0.15 M NaCl)으로 전처리하여 평형을 유지시킨 Mono QTM HR 5/5 컬럼(column)에 적용하고, 10 ml의 버퍼 A + 0.15 M NaCl 버퍼용액으로 워싱(washing)한 후, 0.15 M 내지 0.90 M NaCl을 버퍼 A에 첨가하여 선형 농도구배가 형성된 용액 20ml을 1ml/분의 유속으로 흘러보내 인자 Ⅷ을 용출하였다.
인간 혈장유래인자 Ⅷ (Mono QTM HPLC에 의해서 정제된 것)와 돼지 인자 Ⅷ를 비교하기 위해서, 면역친화도(immunoaffinity)을 이용하여 정제된 돼지 혈장유래인자 Ⅷ을 0.04M Hepes, 5 mM CaCl2, 0.01% Tween-80을 함유하는 용액(pH 7.4)을 사용하여 1:4 비율로 희석한 후 인간 인자 Ⅷ의 경우와 동일한 조건으로 Mono QTM HPLC을 수행하였다. 인간 및 돼지 인자 Ⅷ을 분리하는 이러한 과정은 본 발명이 속하는 기술분야의 당업자에게 잘 알려져 있다.
용출된 컬럼 분획(fraction)에서 일단계 혈액응고 분석법(one-stage coagulation assay)을 이용하여 인자 Ⅷ의 혈액응고 활성도을 측정하였다. 측정된 활성도는 평균하여 흡광도 A280당 단위(unit)로 표현하였다. 하기 표 Ⅱ에 나타낸 바와 같이, 일단계 분석법을 사용했을 때 돼지 인자 Ⅷ은 인간 인자 Ⅷ보다 6배 높은 활성을 나타냈다.
[표 Ⅱ] 인간 및 돼지 인자 Ⅷ의 혈액응고 활성도의 비교
| 혈액응고 활성도 (U/A280) | |
| 돼지 인자 Ⅷ | 21,300 |
| 인간 혈장유래인자 Ⅷ | 3,600 |
| 인간 재조합 Ⅷ | 2,400 |
[실시예 3] 인간 및 돼지 인자 Ⅷ의 안정성 비교
인자 Ⅷ에 대한 일단계 분석의 결과로부터 인자 Ⅷ은 샘플에서 인자 Ⅷa로 활성화되고 형성된 인자 Ⅷa의 활성이 손실될 가능성이 있음을 알 수 있다. 인간 및 돼지 인자 Ⅷ의 안정성은 직접 비교되었다. Mono QTM HPLC (Pharmacia-LKB, Piscataway, N.J.)을 통해서 획득한 샘플을 동일한 농도와 동일한 조성의 버퍼로 희석한 후 트롬빈(thrombin)으로 반응시켰다. 다양한 시간대에서 샘플을 채취하여 이단계 혈액응고 분석(two-stage coagulation assay)에 사용하였다. 2분에서 나타난 피크(peak)에서의 활성도는 인간 인자 Ⅷa보다 돼지 인자 Ⅷa에서 10배 높게 나타났고, 그 이후 활성도는 돼지와 인간 인자 Ⅷa 모두에서 감소하였고 이때 인간 인자 Ⅷa의 활성도가 좀 더 빠른 속도로 감소하였다.
일반적으로, 돼지 인자 Ⅷa가 안정한 형태로 분리되는 조건에서 인간 인자 Ⅷa 분자는 안정한 형태로 분리되지 않는다. 이러한 사실을 증명하기 위해서, Mono QTM HPLC을 통해서 정제한 인간 인자 Ⅷ을 트롬빈으로 활성화시킨 후, 안정한 형태의 돼지 인자 Ⅷa을 생성하는 조건하에서 Mono QTM 양이온 교환수지를 이용하여 HPLC을 수행하였다 (Lollar et al. (1989) Biochemistry 28:666).
총부피 10ml로 하여 인간 인자 Ⅷ 43 ㎍/ml을 0.2 M NaCl, 0.01 M Hepes, 2.5 mM CaCl2을 함유하는 버퍼용액(pH7.4)에 첨가하고 트롬빈 (0.036 μM)로 10분 동안 반응시킨 후, 트롬빈을 완전히 불활성화시키기 위해서 FPR-CH2Cl D-페닐-프로필-아지닐-클로로메틸 케톤 (FPR-CH2Cl D-phenyl-propyl-arginyl-chloromethyl ketone)을 0.2 μM 농도로 첨가하였다. 반응혼합물을 40 mM 2-(N-모포리노)에탄 설폰닉산 (2-(N-morpholino)ethane sulfonic acid, MES)와 5 mM CaCl2을 포함하는 용액 (pH 6.0)으로 1:1 비율로 희석한 후, 2 ml/min의 유속으로 버퍼 B(5 mM MES, 5 mM CaCl2, pH 6.0) + 0.1 M NaCl 용액으로 전처리하여 평형을 유지시킨 Mono STM HR 5/5 HPLC 컬럼 (Pharmacia, Inc)에 적용하였다. 컬럼을 워싱(washing)하지 않고 바로 0.1 M 내지 0.9 M NaCl을 버퍼 B에 첨가하여 선형 농도구배가 형성된 용액 20ml을 1ml/min의 유속으로 흘러보내 인자 Ⅷ을 용출하였다.
이단계 분석(two-stage assay)을 실시한 결과, 혈액응고 활성이 있는 분획은 이러한 조건하에서 하나의 피크를 나타냈다. 피크를 나타낸 분획은 7,500 U/A280의 비활성(specific activity)을 나타냈다. 인자 Ⅷa 피크(peak)를 나타낸 Mono STM 분획을 SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis)을 수행한 후 단백질을 은염색(silver staining)한 결과 인자 Ⅷ의 이종이중체(heterodimeric, A3-C1-C2/A1) 유도체에 상응하는 밴드가 2개 나타났다. A2 단편은 낮은 농도로 존재하기 때문에 은염색(silver staining)시 확인되지 않았지만, 125I로 라벨링했을 때 미세하게 확인되었다.
인간 인자 Ⅷ의 결과와는 반대로, 동일한 조건에서 Mono STM HPLC에 의해서 정제된 돼지 인자 Ⅷa는 1.6x106 U/A280의 비활성(specific activity)을 나타냈다. 돼지 인자 Ⅷa을 SDS-PAGE을 수행하였을 때 A1, A2, A3-C1-C2 서브단위(subunits)에 대응하는 3개의 단편이 확인되었고, 이러한 결과를 통해서 돼지 인자 Ⅷa는 상기 3개의 단편을 포함하고 있음을 알 수 있었다.
인간 인자 Ⅷ은 트롬빈에 의해서 활성화시킨 후 Mono STM HPLC을 이용하여 pH 6.0 버퍼로 용출한 결과에서 알 수 있듯이 안정한 형태의 돼지 인자 Ⅷa을 생성하는 조건하에서도 불안정하다는 것이 증명되었다. 그러나, 미량의 A2 단편이 피크 분획에서 확인되었으나, 혈액응고 활성이 이종이량체(heterodimeric) 인자 Ⅷa가 소량으로 존재하기 때문에 나타난 결과인지 아니면 이종이량체 인자 Ⅷa의 비활성(specific activity)이 낮아서 나타난 결과인지는 이러한 방법으로는 결정할 수 없었다.
이러한 의문점을 해결하려면, A2 서브단위(subunit)가 제거되기 전에 인간 인자 Ⅷ을 분리하는 것이 바람직하다. Mono STM 버퍼의 pH를 5까지 낮추어서 사용하였다. Mono QTM 로 정제한 인간 인자 Ⅷ (0.5 mg)을 물로 희석하여, 0.25M NaCl, 0.01M Hepes, 2.5 mM CaCl2, 0.005% Tween-80로 구성된 용액 (pH 7.4)에 최종농도가 0.25 mg/ml (1 ㎛)이 되도록 첨가하였고 이때 총 부피는 7 ml이었다. 트롬빈을 최종 농도 0.072 ㎛로 첨가하여 3분 동안 반응시켰다. 반응 후 트롬빈은 FPR-CH2Cl (0.2㎛)으로 불활성화 시켰다. 반응혼합물을 40 mM 소디움 아세테이트 (sodium acetate), 5 mM CaCl2, 0.01 % Tween-80으로 구성된 용액 (pH 5.0)을 사용하여 1:1 비율로 희석시킨 후, 2 ml/min의 유속으로 0.01M 소디움 아세테이트, 5 mM CaCl2, 0.01 % Tween-80으로 구성된 버퍼용액 (pH 5.0) + 0.1 M NaCl 용액으로 전처리하여 평형을 유지시킨 Mono STM HR 5/5 HPLC 컬럼에 적용하였다. 컬럼을 워싱(washing)하지 않고 바로 0.1 M 내지 1.0 M NaCl을 상기 버퍼용액에 첨가하여 선형 농도구배가 형성된 용액 20ml을 1ml/min의 유속으로 흘러보내 인자 Ⅷ을 용출하였다. 수집된 분획을 SDS-PAGE 및 은염색 (silver staining)을 수행하였을 경우 측정가능한 양을 포함하는 피크 분획에서 혈액응고 활성이 회복되는 결과를 얻었다. pH 6.0에서 피크 분획은 7,500 U/A280의 비활성을 나타냈으나 pH 5.0에서는 보다 10배 높은 비활성 (specific activity)(75,000 U/A280)을 나타냈다. pH 6.0에서 분리한 돼지 인자 Ⅷa가 4 ℃에서 영원히 안정한 것과는 반대로, 인간 인자 Ⅷa의 활성은 Mono STM 컬럼에서 용출된 후 몇 시간동안 시간이 경과함에 따라서 감소되었다. pH 5.0에서 정제된 인자 Ⅷa의 비활성은 분리 후 즉시 측정하였고 이때 돼지 인자 Ⅷa의 5 % 정도로 나타났고, 이러한 결과를 통해서 실질적인 해리현상이 분석전에 이미 일어났다는 것을 알 수 있었다.
이러한 결과를 통해서 인간 및 돼지 인자 Ⅷa은 3개의 서브단위 (A1, A2, A3-C1-C2)로 구성되어있다는 것을 알 수 있다. A2 서브단위가 해리되면 생리적 이온강도, pH, 농도와 같은 조건에서 인간 및 돼지 인자 Ⅷa은 모두 활성을 잃게된다. 돼지 인자 Ⅷa에서 A2 서브단위가 더 강하게 결합하고 있기 때문에 돼지 인자 Ⅷa는 어떤 조건에서 상대적으로 안정하다.
[실시예 4] 돼지 인자 Ⅷ의 A2 도메인를 인코딩하는 DNA의 분리 및 이의 염기서열 결정
돼지 인자 Ⅷ의 B 도메인과 A2 도메인의 일부분을 인코딩하는 뉴클레오타이드 서열은 기존에 밝혀졌다 (Toole et al. (1986) Proc. Natl. Acad. Sci. USA 83:5939-5942). 돼지 인자 Ⅷ의 A2 도메인 전체에 대한 cDNA 및 예상되는 아미노산 서열 (각각 서열번호 3과 4에 기재)은 본 발명에서 밝혔다.
돼지 인자 Ⅷ의 A2 도메인은 돼지 췌장에서 분리한 총 RNA (total RNA)을 이용하여 역전사 및 PCR을 수행함으로써 클로닝하였고, 이때 인간 인자 Ⅷ의 공지된 cDNA 서열에 기초하여 제작한 복합 프라이머 (degenerate primers) 및 돼지 인자 Ⅷ의 일부 서열에 기초하여 제작한 정확한 돼지 프라이머를 이용하였다. 1 kb의 PCR 산물을 수득하였고 BluescriptTM (Stratagene) 파지미드(phagemid) 벡터에 삽입하여 증폭하였다.
디데옥시 서열분석방법 (dideoxy sequencing)을 이용하여 클로닝한 돼지 A2 도메인의 전체 염기서열을 결정하였고, cDNA 및 예상되는 아미노산 서열은 서열번호 3과 4에 각각 기재된 바와 같다.
[실시예 5] 돼지 인자 Ⅷ을 인코딩하는 DNA의 완전한 서열
클레나우 단편 (Klenow fragment), 인산화된 Cla I 링커(linker), Not I 링커, T4 리가제 (ligase), Taq DNA 중합효소는 Promega 사(Madison, Wisconsin)에서 구입하여 사용하였다. 폴리뉴클레오타이드 키나제(polynucleotide kinase)는 Life Technologies 사 (Gaithersburg, Maryland)에서 구입하여 사용하였다. γ32P-ATP (Redivue, 〉5000 Ci/mmol)은 Amersham 사에서 구입하여 사용하였다. pBluescript ⅡKS 및 E. coli Epicurean XL1-Blue 세포는 Stratagene 사(La Jolla, California)에서 구입하여 사용하였다. 합성 올리고뉴클레오타이드(synthetic oligonucleotides)는 Life Technologies 사 또는 Cruachem 사에서 구입하였다. 5'-인산화된(phosphorylated) 프라이머는 PCR 산물을 클로닝할 때 사용하였다. PCR(중합효소 연쇄 반응, polymerase chain reaction)을 수행하여 돼지 인자 Ⅷ (fⅧ)의 cDNA 또는 게놈 DNA을 증폭할 때 프라머로서 사용된 올리고뉴클레오타이드의 뉴클레오타이드(nucleotide, nt)의 수는 인간 fⅧ의 cDNA를 참고하여 결정하였다 (Wood et al. (1984) supra).
돼지 췌장 총 RNA(total RNA)는 산 구아니디니움 티오시아네이트(acid guanidinium thiocyanate)-페놀-클로로포름으로 정제하여 분리하였다 (Chomczynski et al. (1987) Anal. Biochem. 162:156-159). 돼지 cDNA는 별다른 지시사항이 없으면 MoMLV (Moloney murine leukemia virus) 역전사효소(reverse transcriptase, RT) 및 프라이머로서 무작위 헥사머(random hexamer) (First-Strand cDNA Synthesis Kit, Pharmacia Biotech)를 이용하여 돼지 췌장 총 RNA로부터 합성하였다. RT 반응액에는 45 Mm Tris-Cl(pH 8.3), 68 mM KCl, 15 mM DTT, 9 mM MgCl2, 0.08 mg/ml 소혈청 알부민 및 1.8 mM 데옥시뉴클레오타이드 트리포스페이트(deoxynucleotide triphosphate, dNTP)이 함유되었다. 돼지 게놈 DNA (genomic DNA)는 일반적인 방법(Strauss, W. M. (1995) In Current Protocols in Molecular Biology, F. M. Ausubel et al., editors, John Wiley & Sons, pp. 2.21-2.2.3)을 이용하여 췌장에서 분리하였다. 아가로스 겔로부터 DNA를 GenecleanⅡ(bio 101) 또는 QuiexⅡ Gel Extraction Kit (Qiagen)을 이용하여 정제하였다.
PCR 반응은 Hybaid OmniGene thermocycler라는 PCR 기기에서 수행하였다. 0.6mM MgCl2, 0.2 mM dNTPs, 0.5 μM 올리고뉴클레오타이드 프라이머, 50 U/ml 중합효소 및 0.1 부피의 첫 번째 사슬 cDNA 반응 혼합물을 함유한 반응액에서 Taq DNA 중합효소을 사용하여 PCR 반응을 수행하였다. 특별한 경우를 제외하고는 PCR 산물을 겔에서 정제하여 클레나우 단편(Klenow fragment)을 이용하여 양 말단을 평활 말단(blunt end)으로 만든 후 에탄올로 침전시켰다. 이와 같이 수득한 PCR 산물은 탈인산화된 pBluescript ⅡKS(-)의 EcoR V 자리에 삽입하거나, T4 리가제(ligase)을 이용하여 세파크릴(sephacryl) S 400 크로마토그래피로 정제한 인산화된 ClaⅠ링커(linker)에 연결하여 탈인산화된 pBluescript ⅡKS(-)의 ClaⅠ자리에 삽입하였다. 여기서 연결(ligation)은 별다른 지시사항이 없으면 T4 DNA 리가제(Rapid DNA ligation kit, Boehringer Mannheim)을 이용하여 실시하였다. 인서트(insert)를 함유하는 pBluescript ⅡKS(-) 플라스미드는 형질전환을 통해서 E. coli Epicurean XL1-Blue 세포에 도입하였다.
플라스미드 DNA의 염기서열은 Applied Biosystems 373a 자동 DNA 서열분석기, PRISM 염색약 중단 키트(PRISM dye terminator kit)를 이용하여 결정하거나, Sequenase v. 2.0 sequencing kit (Amersham Corporation)을 이용하여 수동으로 직접 반응시켜 결정하였다. 이러한 PCR 산물의 염기서열을 직접 결정하는 방법(direct sequencing)은 싸이클 씨퀀싱 프로토콜(cycle sequencing protocol)(dsDNA Cycle Sequencing System, Life Technologies)에 따라서 32P로 라벨링된 올리고뉴클레오타이드을 이용하여 수행하였다.
5' UTR 서열, 신호 펩타이드 및 A1 도메인 코돈을 포함하는 돼지 fⅧ cDNA 클론의 분리
암돼지 췌장에서 분리한 총 RNA(total RNA)을 사용하여 5'-RACE (5'-rapid amplification of cDNA ends) 프로토콜(Marathon cDNA Amplification, Clontech, Version PR55453)에 따라서 네스티드(nested) RT-PCR을 수행하여 5' UTR 서열에서 A1 도메인 코돈을 포함하는 돼지 fⅧ cDNA를 증폭하였고, 이때 첫 번째 cDNA 사슬을 합성하기 위해 록-도킹(lock-docking) 올리고(dT) 프라이머를 사용하였고 (Borson, N.D. et al. (1992) PCR Methods Appl. 2:144-148), 두 번째 cDNA 사슬을 합성할 때 E. coli DNA 중합효소Ⅰ을 사용하였고, 5' 말단이 연장된 이중사슬 어댑터(adaptor) (서열번호 5: 5'-CTA ATA CGA CTC ACT ATA GGG CTC GAG CGG CCG CCC GGG CAG GT-3
3'-H2N-CCCGTCCA-PO4-5'을 사용하여 연결(ligation)하였고, 어댑터의 3' 말단은 프라이머가 비특이적으로 결합하는 것을 감소시키기 위하여 아미노기로 블록시켰고 3' 말단에서 있는 8개 뉴클레오타이드와 상보적으로 구성되어 있다 (Siebert, P.C., et al. (1995) Nucleic. Acids. Res. 23:1087-1088). 첫 번째 PCR은 센스 프라이머(sense primer)로서 어댑터-특이적 올리고뉴클레오타이드 (서열번호 6: 5'-CCA TCC TAA TAC GAC TCA CTA TAG GGC-3' (AP1), 안티센스 프라이머(antisense primer)로서 돼지 fⅧ A2 도메인-특이적 올리고뉴클레오타이드 (서열번호 7: 5'-CCA TTG ACA TGA AGA CCG TTT CTC-3' (nt 2081-2104)을 이용하여 수행하였다. 두 번째 PCR은 센스 프라이머(sense primer)로서 네스티드(nested) 어댑터-특이적 올리고뉴클레오타이드 (서열번호 8: 5'-ACT CAC TAT AGG GCT CGA GCG GC-3' (AP2), 안티센스 프라이머(antisense primer)로서 돼지 fⅧ A2 도메인-특이적 올리고뉴클레오타이드 (서열번호 9: 5'-GGG TGC AAA GCG CTG ACA TCA GTG-3' (nt 1497-1520))을 이용하여 수행하였다. PCR 반응은 항체에 의해서 매개되는 핫 스타트(hot start) 방법(Kellogg, D.E. et al. (1994) BioTechniques 16:1134-1137)을 이용하는 시판 키트 (Advantage cDNA PCR core kit)을 사용하여 수행하였다. PCR 조건은 94 ℃에서 60초에서 전처리하는 변성단계를 거친 후, 변성단계: 94 ℃에서 30초, 어닐링(annealing)단계: 60 ℃에서 30초, 연장단계: 68 ℃에서 4분으로 구성되는 싸이클을 첫 번째 PCR의 경우 30회, 두 번째 PCR의 경우 25회 반복 실시하였다. PCR 수행결과 약 1.6 kb의 산물을 획득하였고, 이는 약 150 bp을 연장하여 증폭된 5' UTR까지 포함하는 단편과 일치하는 것이다. PCR 산물은 ClaⅠ 링커(linker)를 이용하여 pBluescript에 클로닝하였다. 4개의 클론에 있는 인서트(insert)의 서열은 양방향 모두에서 결정되었다.
이러한 클론의 염기서열을 결정한 결과, 5' UTR, 신호 펩타이드, A1 도메인, A2 도메인의 일부분을 포함하는 것으로 확인되었고, 이들 4 군데중 적어도 3 군데의 서열은 일치(concensus) 하였다. 그러나, 클론은 평균 4개의 돌연변이를 포함하고 있었고, 이는 아마 PCR 반응을 여러 회 반복수행함으로써 일어난 결과일 것으로 판단된다. 따라서 본 발명자들은 확보된 서열을 다시 확인하기 위하여 또다른 PCR 산물을 합성하고 이를 발현벡터에 클로닝하기 위하여, 센스 가닥(sense strand) 인산화된 PCR 프라이머를 디자인하기 위해서 신호 펩타이드 부분의 서열을 이용하였다 (서열 번호 10: 5'-CCT CTC GAG CCA CCA TGT CGA GCC ACC ATG CAG CTA GAG CTC TCC ACC TG-3' (RENEOPIGSP). 짙은 글씨로 된 서열은 시작 코돈(start codon)이다. 5' 말단부터 시작코돈까지의 서열은 fⅧ의 발현에 사용된 포유세포용 발현벡터 ReNeo의 삽입부위의 5' 쪽과 동일한 서열(Lubin et al. (1994) supra)이고, XhoⅠ 절단부위 서열(밑줄친 부분)을 포함한다. RENEOPIGSP 및 nt 1497-1520 올리고뉴클레오타이드는 암돼지 췌장 cDNA을 주형으로 사용하는 Taq DNA 중합효소에 의한 PCR 반응시 프라이머로 사용하였다. 몇 개의 제조사에서 구입한 DNA 중합효소을 이용하여 PCR 산물을 획득하였다. 94 ℃에서 4분 동안 전처리하여 변성시킨 후, 변성단계: 94 ℃에서 1분, 어닐링(annealing)단계: 55 ℃에서 2분, 연장단계: 72 ℃에서 2분으로 구성되는 사이클을 35회 반복 실시한 후, 마지막으로 72 ℃에서 5분동안 연장 단계를 실시하였다. PCR 산물은 ClaⅠ 링커(linker)를 이용하여 pBluescript에 클로닝하였다. 2개의 클론을 선택하여 인서트(insert)의 염기서열을 양방향 모두에서 결정하였고 상기 일치(concensus) 서열과 일치하였다.
A3 도메인과 C1 도메인, 및 C2 도메인의 일부분을 포함하는 돼지 fⅧ cDNA 클론의 분리
먼저, 돼지 췌장 총 RNA(total RNA)이용하여 획득한 2개의 RT-PCR 산물을 클로닝하였고, 이들은 B-A3 도메인 단편(nt 4519-5571)과 C1-C2 도메인 단편(nt 6405-6990)이다. 획득한 C2 도메인의 3' 말단은 fⅧ에 끝에 존재하는 엑손인 엑손 26 부위까지 포함하였다. B-A3 산물은 돼지-특이적 B 도메인 프라이머 (서열번호 11: 5'-CGC GCG GCC GCG CAT CTG GCA AAG CTG AGT T-3' 을 사용하여 획득한 거이고, 서열번호 11에서 밑줄친 부분은 인간 fⅧ에서 nt 4519-4530의 염기서열과 대응하는 돼지 fⅧ의 서열과 일치한다. 올리고뉴클레오타이드의 5' 영역은 클로닝시 이용하기 위한 NotⅠ부위을 포함한다. B-A3 산물을 생산하는 데 사용된 안티센스 프라이머 (서열번호 12: 5'-GAA ATA AGC CCA GGC TTT GCA GTC RAA-3' 는 인간 fⅧ cDNA에서 nt 5545-5571 염기서열에 대해 반대방향에서 상보적인 서열(reverse complement)에 기초하여 디자인하였다. PCR 반응액은 50 mM KCl, 10 mM Tris-Cl (pH 9.0), 0.1 % Triton X-100, 1.5 mM MgCl2, 2.5 mM dNTPs, 20 μM 프라이머, 25 units/ml Taq DNA 중합효소 및 20분의 1 부피의 RT 반응 혼합물을 함유한다. 94 ℃에서 3분 동안 전처리하여 변성시킨 후, 변성단계: 94 ℃에서 1분, 어닐링(annealing)단계: 50 ℃에서 2분, 연장단계: 72 ℃에서 2분으로 구성되는 사이클을 30회 반복 실시하였다. PCR 산물은 T4 DNA 키나제(kinase)를 이용하여 인산화하여 NotⅠ 링커(linker)로 연결하였다. PCR 단편은 NotⅠ으로 절단하여 pBluescript ⅡKS(-)의 NotⅠ자리에 클로닝한 후, 이 벡터로 XL1-Blue 세포를 형질전환시켰다.
C1-C2 산물을 획득하기 위해서 공지된 인간 fⅧ cDNA 서열을 이용하여 센스 및 안티센스 프라이머 (각각 서열번호 13과 14, 서열번호 13: 5'-AGG AAA TTC CAC TGG AAC CTT N-3' (nt 6405-6426); 서열번호 14: 5'-CTG GGG GTG AAT TCG AAG GTA GCG N-3' (nt 6966-6990의 역방향으로 상보적인 서열(reverse complement)을 제작하였다. PCR은 B-A2 산물의 경우와 동일한 조건에서 실시하였다. 획득한 PCR 단편은 Prime PCR Cloner Cloning System (5 Prime-3 Prime, Inc., Boulder, Colorado)을 이용하여 pNOT 클로닝 벡터에 삽입하고 JM109 세포에서 증폭하였다.
B-A3 및 C1-C2 플라스미드를 부분적으로 시퀀싱(sequencing)하여 돼지-특이적 센스 및 안티센스 올리고뉴클레오타이드(각각 서열번호 15와 16, 서열번호 15: 5'-GAG TTC ATC GGG AAG ACC TGT TG-3' (nt 4551-4573); 서열번호 16: 5'-ACA GCC CAT CAA CTC CAT GCG AAG-3' (nt 6541-6564)를 합성하는 데 이용하였다. 이러한 올리고뉴클레오타이드를 프라이머로 사용하여 Clontech Advantage cDNA PCR kit을 사용하면서 RT-PCR을 수행하여 2013 bp의 RT-PCR 산물을 획득하였다. 인간 fⅧ의 nt 4551-6564에 대응하는(correspond to) 서열을 가지는 상기 RT-PCR 산물은 경사슬 활성화 펩타이드(light chain activation peptide)(nt 5002-5124), A3 도메인 (nt 5125-6114), C1 도메인의 대부분(nt 6115-6573)에 대응하는 영역을 포함한다. C1-C2 클론의 염기서열은 결정되었고, 인간 및 돼지 cDNA의 서열은 nt 6565부터 C1 도메인의 3' 말단까지 동일하였다. PCR 산물은 pBluescriptⅡKS(-)의 EcoRⅤ자리에 클로닝하였다. 4군데중 3군데에서 서열이 일치(concensus)하였다.
C2 도메인의 3' 쪽 절반을 포함하는 돼지 fⅧ cDNA 클론의 분리
인간 fⅧ의 C2 도메인(nt 6574-7053)은 엑손 24부터 26까지을 포함한다 (Gitschier J. et al. (1984) Nature 312:326-330). 인간 fⅧ의 엑손 26은 nt 6901-8858에 위치하며 1958 bp로 구성된다. 또한, C2 도메인은 1478 bp의 3' 쪽에 번역이 되지 않는 서열(3' untranslated sequence, 3' UTR)을 포함하고 있다. C2 도메인의 3' 영역과 3' UTR 에 대응하는 엑손 26 cDNA을 클로닝하기 위해서 3' RACE (Siebert et al. (1995) supra), 역 PCR (inverse PCR) (Ochman, H. et al. (1990) Biotechnology (N.Y) 8:759-760), 제한효소 인식서열 PCR (Sarkar, G. et al. (1993) PCR Meth. Appl. 2:318-322), "unpredictably primed" PCR (Dominguez, O. et al. (1994) Nucleic. Acids res. 22:3247-3248)을 수행하였고, 돼지 간 cDNA 스크리닝은 실패하였다. 돼지 fⅧ cDNA의 5' 영역을 성공적으로 획득할 때 사용하였던 어댑터(adaptor)가 연결된 동일한 이중사슬(double-stranded) cDNA 라이브러리(library)을 이용하여 3' RACE을 실시하였다. 따라서 이러한 방법의 실패는 엑손 26에 대응하는 cDNA가 존재하지 않기 때문에 발생한 것은 아니다.
표적 유전자 워킹 PCR (targeted gene walking PCR) 방법 (Parker, J.D. et al. (1991) Nucleic. Acids. Res. 19:3055-3060)을 이용하여 C2 도메인의 3' 쪽의 절반부분을 클로닝하였다. 돼지-특이적 센스 프라이머(서열번호 17: 5'-TCA GGG CAA TCA GGA CTC C-3' (nt 6904-6924))는 처음에 확보한 C2 도메인 서열에 기초하여 제작하였고 실험실에서 보유하고 있는 올리고뉴클레오타이드 중 비특이적 "워킹(walking)" 프라이머와 함께 PCR 반응에 사용하였다. PCR 산물은 프라이머 연장 분석법(primer extension analysis)(Parker et al. (1991) BioTechniques 10:94-101)에 따라서 말단이 32P로 라벨링된 돼지-특이적 내부 프라이머(32P-end labelled porcine-specific internal primer, 서열번호 18: 5'-CCG TGG TGA ACG CTC TGG ACC-3' (nt 6932-6952))을 사용하면서 획득하였다. 흥미롭게도, 40개의 비특이적 프라이머를 조사했을 때, 단지 2개에서만 프라이머 연장 분석시 의미있는 산물이 생성되었고, 이 2개의 산물은 C2 도메인의 3' 말단과 동일한 서열이거나 복합서열이었다: 서열번호 19: 5'-GTA GAG GTC CTG TGC CTC GCA GCC-3' (nt 7030-7053; 서열번호 20: 5'-GTA GAG STS CTG KGC CTC RCA KCC YAG-3' (nt 7027-7053). 이러한 프라이머는 처음에 일반적인 RT-PCR을 수행하기 위해서 디자인한 것이었으나 EtBr 염색시 관찰될 수 있을 만큼의 충분한 양의 산물이 생성되지 못했다. 그러나, 좀더 민감한 프라이머 연장 분석법을 이용한 결과 PCR 산물을 확인할 수 있었고, 겔에서 정제하여 바로 염기서열을 결정하였다. 이 PCR 산물은 돼지 fⅧ의 3' 영역의 nt 7026까지의 서열을 포함한다.
염기서열을 좀더 확보하기 위하여 상기에서 설명한 5'-RACE 수행시 사용한 어댑터가 연결된 이중사슬 cDNA 라이브러리(library)를 이용하여 생성된 네스티드(nested) PCR 산물에 대해서 프라이머 연장 분석을 실시하였다. 첫 번째 PCR 반응은 돼지의 정확한 프라이머(서열번호 21: 5'-CTT CGC ATG GAG TTG ATG GGC TGT-3' (nt 6541-6564)와 AP1 프라이머을 사용하여 실시하였다. 두 번째 반응은 서열번호 22로 표시되는 프라이머(서열번호 22: 5'-AAT CAG GAC TCC TCC ACC CCC G-3' (nt 6913-6934)와 AP2 프라이머를 사용하여 실시하였다. PCR 산물을 직접 염기서열을 결정하여 C2 도메인의 3' 말단(nt 7053)까지의 서열을 확보하였다. C2 도메인의 염기서열은 3' 말단에 위치한 nt 7053의 염기를 제외하고는 각 위치에서 하나의 염기로 표시되었다. PCR 반응을 반복수행하여 분석한 결과 nt 7053 위치에서 염기는 A또는 G, 또는 A/G로 나타났다.
두 개의 다른 프라이머(서열번호 23: 5'-GGA TCC ACC CCA CGA GCT GG-3' (nt 6977-6996); 서열번호 24: 5'-CGC CCT GAG GCT CGA GGT TCT AGG-3' (nt 7008-7031)를 이용하여 3' UTR까지 염기서열을 결정하였다. 3' UTR의 15bp의 서열을 더 확보하였고 이 서열은 몇 군데서 염기가 정확하지 않다. 몇 개의 안티센스 프라이머을 3' UTR의 가장 바람직한 서열을 기초로 하여 합성하였고, 이러한 프라이머는 3' 말단에 있는 TGA 스탑 코돈(stop codon)의 역방향의 상보적서열(reverse complement)을 포함한다. 특이적 센스 프라이머(서열번호 25: 5'-AAT CAG GAC TCC TCC ACC CCC G-3' (nt 6913-6934))와 3' UTR 안티센스 프라이머(서열번호 26: 5'-CCT TGC AGG AAT TCG ATT CA-3' , 돼지 췌장에서 분리한 게놈 DNA와 돼지 췌장에서 분리한 cDNA를 이용하여 PCR을 수행한 후 아가로스 겔 전기영동 및 EtBr 염색하여 PCR 산물을 확인하였다. 클로닝을 할 수 있을 만큼의 충분한 양을 확보하기 위해, 두 번째 PCR을 네스티드(nested) 센스 프라이머(서열번호 27: 5'-CCG TGG TGA ACG CTC TGG ACC-3' (nt 6932-6952))와 첫 번째 반응에서 사용한 것과 동일한 안티센스 프라이머를 사용하여 수행하였다. 141bp의 PCR 산물을 pBluescript Ⅱ KS(-)의 EcoRⅤ 자리에 클로닝하였다. 게놈 DNA에서 유래한 PCR 산물을 함유하는 클론 3개와 cDNA에서 유래한 PCR 산물을 함유하는 클론 3개에 대해서 양방향에서 염기서열을 결정하였다. nt 7045 위치에서의 염기를 제외한 서열은 서로 동일하였고, nt 7045의 염기는 게놈 DNA의 경우 A였고, cDNA의 경우 G로 나타났다.
인간, 돼지, 마우스 fⅧ의 DNA 서열의 다양한 비교 (Fig. 1A-1H)
신호 펩타이드(signal peptide) A1, A2, A3, C1 및 C2 도메인 부분의 종간 서열 비교는 CLUSTALW 프로그램(Thompson, J.D. et al. (1994) Nucleic. Acids. Res. 22:4673-4680)이용하여 실시하였다. 여기서 갭 오픈(gap open)과 갭 연장(gap extension) 벌칙(penalty)은 각각 10과 0.05를 기본값으로 하였다. 인간, 마우스 및 돼지의 B 도메인의 서열은 이미 비교된 바 있다 (Elder et al. (1993) supra). 인간 A2 도메인은 서열번호 2에 있는 373-740 위치의 아미노산 서열과 일치한다. 돼지 A2 아미노산 서열은 서열번호 4에 나타낸 바와 같고, 마우스 A2 도메인 아미노산 서열은 서열번호 28 (아미노산 392-759)에 나타낸 바와 같다.
[실시예 6] 활성형태의 B 도메인이 없는 재조합 돼지 인자 Ⅷ (HB-)
시트레이트가 함유된(citrated) 혈우병 A 환자의 혈장 및 정상인의 혈장은 George King Biomedical 사에서 구입하여 사용하였다. 소혈청(fetal bovine serum), 제네티신(geneticin), 페니실린(penicillin), 스트렙토마이신(streptomycin), DMEM/F12 배지 및 AIM-V 배지는 Life Technologies 사에서 구입하여 사용하였다. Taq DNA 중합효소는 Promega 사에서 구입하였다. Vent DNA 중합효소는 New England Biolabs 사에서 구입하였다. Pfu DNA 중합효소와 파지미드(phagemid) pBlueScriptⅡKS(-)는 Stratagene 사에서 구입하였다. 합성 올리고뉴클레오타이드는 Life Technologies 사 또는 Cruachem 사에서 구입하였다. 제한효소는 New England Biolabs 사 또는 Promega 사에서 구입하였다. 5' 인산화된 프라이머(5' phosphorylated primers)는 PCR 산물을 클로닝하고자 할 때 사용하였다. 돼지 fⅧ cDNA 또는 게놈 DNA의 PCR 증폭시 사용된 올리고뉴클레오타이드의 뉴클레오타이드(nt)의 번호는 인간 fⅧ cDNA을 참고하여 결정하였다 (Wood et al. (1984) Nature 312:330-337). fⅧ 발현벡터(HB-/ReNeo)는 Biogen 사에서 구입하였다. HB-/ReNeo 벡터는 앰피실린(ampicillin) 및 제네티신 저항성 유전자, B 도메인 전체가 없는 인간 fⅧ cDNA 서열(트롬빈에 의해서 생성된 Ser741-Arg1648 절단 단편)을 함유하고 있다. ReNeo 벡터에 삽입된 fⅧ 인서트(insert)의 3' 말단에 있는 fⅧ C2 도메인 cDNA에서 돌연변이를 간단하게 유도하기 위해서, NotⅠ서열을 SOE 돌연변이(splicing-by-overlap extension mutagenesis)에 의해서 HB-/ReNeo 벡터의 스탑코돈(stop codon)의 3' 쪽에 있는 두 염기사이에 도입하였고 (Horton, R.M. et al. (1993) Methods Enzymol. 217:270-279), HB-/ReNeo/NotⅠ으로 명명하였다.
총 RNA (total RNA)는 산 구아니디니움 티오시아네이트(acid guanidinium thiocyanate)-페놀-클로로포름으로 정제하여 분리하였다 (Chomczynski et al. (1987) Anal. Biochem. 162:156-159). cDNA는 MoMLV (Moloney murine leukemia virus) 역전사효소(reverse transcriptase, RT) 및 프라이머로서 무작위 헥사머(random hexamer) (First-Strand cDNA Synthesis Kit, Pharmacia Biotech)를 이용하여 mRNA로부터 합성하였다. 플라스미드 DNA는 Qiagen Plasmid Maxi Kit (Qiagen 사)을 이용하여 정제하였다. PCR 반응은 Hybaid OmniGene thermocycler에서 Taq, Vent 또는 Pfu DNA 중합효소를 이용하면서 수행하였다. PCR 산물은 겔에서 정제하여 에탄올로 침전시킨 후, T4 DNA 리가제(ligase)(Rapid DNA ligation kit, Boehringer Mannheim)을 이용하여 플라스미드 DNA에 삽입하였다. 인서트(insert)를 포함하는 플라스미는 형질전환을 통해서 E. coli Epicurean XL1-Blue 세포에 도입하였다. 클로닝된 모든 새로운 fⅧ DNA 서열은 디에옥시 서열결정 방법(dideoxy sequencing)에 따라서 Applied Biosystems 373a 자동 DNA 서열분석기, PRISM 염색약 중단 키트(PRISM dye terminator kit)를 이용하여 결정하였다.
돼지 C2 도메인을 포함하는 혼성 fⅧ 발현벡터(HP20)의 제조
공지된 돼지 fⅧ DNA 서열(Healey, J.F. et al. (1996) Blood 88:4209-4214)을 기초로 하여 제작한 프라이머 및 췌장 총 RNA(total RNA)를 사용하여 RT-PCR을 수행하였고, C1 도메인의 3' 말단 및 C2 도메인 전체에 해당하는 돼지 fⅧ DNA를 플라스미드 pBluescript에 클로닝하였다. 이 벡터와 HB-/ReNeo 벡터를 주형으로 사용하여 SOE 돌연변이에 의해서 인간 C1와 돼지 C2 도메인을 융합시킨 후 pBluescript에 삽입하였다. 이 플라스미드에서 C1-C2 단편을 ApaⅠ과 NotⅠ을 이용하여 잘라낸 후 ApaⅠ과 NotⅠ으로 처리된 HB-/ReNeo/NotⅠ벡터에 삽입하였고, 결과 생성된 발현벡터를 HP20/ReNeo/NotⅠ으로 명명하였다.
B 도메인이 소실되고 돼지 경사슬(light chain)을 포함하는 혼성 인간/돼지 fⅧ 발현벡터(HP18)의 제조
인간 fⅧ 경사슬(light chain)은 Asp1649에서 Tyr2332까지의 아미노산 잔기로 구성되어 있다. 혼성 인간/돼지 fⅧ를 포함하는 벡터 HP18을 제조하기 위해서 HB-벡터에서 이 부분을 이에 대응하는 돼지 fⅧ cDNA로 치환하였다. 여기서 돼지 A2, A3, C1 도메인 및 C2 도메인의 일부분에 대한 PCR 산물로 HP20 벡터에서 이에 대응하는 부분을 치환하였다. 벡터제조를 용이하게 하기 위하여, SOE 돌연변이 방법(SOE mutagenesis)을 이용하여 동의적(synonymous) AvrⅡ부위를 HP20 벡터에 있는 A2와 A3 도메인의 연결부위에 있는 nt 2273 위치에 도입하였다.
B 도메인이 소실되고 돼지 신호 펩타이드, A1 도메인, A2 도메인을 포함하는 혼성 인간/돼지 fⅧ 발현벡터(HP22)의 제조
인간 fⅧ 신호 펩타이드, A1 도메인, A2 도메인은 Met(-19)-Arg740의 아미노산 잔기로 구성되어 있다. 발현벡터 HP22을 제조하기 위해서 HB-벡터에서 이 부분을 이에 대응하는 돼지 fⅧ cDNA로 치환하였다. 또한, SOE 돌연변이 방법(SOE mutagenesis)을 이용하여 동의적(synonymous) AvrⅡ부위를 HP22 벡터에 있는 A2와 A3 도메인의 연결부위에 있는 nt 2273 위치에 도입하였다. HP22 벡터는 pBlueScript내에서 돼지 신호 펩타이드-A1-A2의 일부분 단편(Healy et al. (1996) supra)을 돼지 A2 도메인을 포함하고 B 도메인이 소실된 혼성 인간/돼지 fⅧ (HP1로 명명됨) (Lubin et al. (1994) supra)을 융합함으로써 제조되었다.
B 도메인이 소실된 돼지 fⅧ 발현벡터(PB
-
)의 제조
HP18/BS(+AvrⅡ)의 SpeⅠ/NotⅠ 단편을 AvrⅡ/NotⅠ으로 절단한 후 AvrⅡ/NotⅠ으로 절단된 HP22/BS(+AvrⅡ)에 연결(ligation)하여 벡터 PB-/BS(+AvrⅡ)을 제조하였고 이 벡터는 B 도메인 전체가 소실된 돼지 fⅧ로 구성된다. PB- 벡터는 PB-/BS(+AvrⅡ)의 XbaⅠ/NotⅠ 단편을 HP22/ReNeo/NotⅠ(+AvrⅡ)에 연결함으로써 ReNeo에 클로닝하였다.
재조합 fⅧ 분자의 발현
PB-/ReNeo/NotⅠ(+AvrⅡ)와 HP22/ReNeo/NotⅠ(+AvrⅡ)을 상기에서 설명한 바와 같이 일시적 형질전환(transient transfection)을 통해서 COS 세포에 도입하여 발현시켰다 (Lubin, I.M. et al. (1994) J. Biol. Chem. 269:8639-8641). HB-/ReNeo/NotⅠ로 형질전환된 세포와 및 DNA을 넣지 않고 (mock) 형질전환된 세포를 대조구로 사용하였다.
PB-, HP22, HB- 발현벡터의 fⅧ 활성은 다음과 같이 발색측정법(chromogenic assay)을 이용하여 측정하였다. COS 세포 배양시 상층액을 채취한 후 여기에 함유되어 있는 fⅧ을 10 nM 인자 Ⅸa, 425 nM 인자 Ⅹ 및 50 μM 단일박막 포스파티딜세린-포스파지딜콜린(25/75 w/w) 소포 (unilamellar phosphatidylserine-phosphatidylcholine vesicles)의 존재 하에서 0.15 M NaCl, 20 mM HEPES, 5 mM CaCl2, 0.01 % Tween-80으로 구성된 용액 (pH 7.4)에 함유된 40 nM 트롬빈으로 활성화시켰다. 5분 후, 0.05 M EDTA와 100 nM 재조합 데설라토리루딘(desulfatohirudin)를 첨가하여 반응을 종결시키고, 반응결과 생성된 인자 Ⅹa의 활성을 발색 기질 측정법(chromogenic substrate assay)을 이용하여 측정하였다. 발색 기질 측정시, 0.4 mM 스펙트로자임(spectrozyme) Ⅹa를 첨가하고 405 nM에서 흡광도를 측정함으로써 파라-니트로아닐이드(para-nitroanilide)의 방출속도를 측정하였다.
본 실험에서 형질전환은 각 케이스마다 두 개씩 실시하였고 배양 상층액에서 fⅧ의 활성도는 다음과 같다 (분당 405 nm에서의 흡광도)
HB-: 13.9
PB-: 139
HP22: 100
mock: ＜0.2
이러한 결과를 통해서 B 도메인이 소실된 돼지 fⅧ과 A1과 A2 도메인을 포함하고 B 도메인이 소실된 fⅧ은 활성이 있음을 알 수 있었고, 따라서 B 도메인이 소실된 인간 fⅧ보다 활성이 우수함을 알 수 있었다.
PB-을 헤파린-세파로스(heparin-Sepharose)크로마토그래피를 이용하여 부분적으로 정제하고 농축시켰다. 헤파린-세파로스(10 ml)을 0.075 M NaCl, 10 mM HEPES, 2.5 mM CaCl2, 0.005 % Tween-80, 0.02 % 소디움 아지드(sodium azide)로 구성된 용액(pH 7.4)으로 평형을 유지시킨 후, PB-을 발현시키는 세포의 배지(100-200 ml)을 헤파린-세파로스에 적용하고, 소디움 아지드가 첨가되지 않은 평형 버퍼(equilibration buffer) 30 ml을 사용하여 세척하였다. 0.65 M NaCl, 20 mM HEPES, 5 mM CaCl2, 0.01 % Tween-80로 구성된 용액을 이용하여 PB-을 용출시키고 -80 ℃에 저장하였다. fⅧ의 혈액응고 활성 효율은 전형적으로 50-75 %였다.
B 도메인이 소실된 돼지 fⅧ(PB
-
)의 안정적 발현(stable expression)
형질전환된 세포주는 10 % 소혈청(FBS), 50 U/ml 페니실린, 50 ㎍/ml 스트렙토마이신을 함유하는 Dulbecco's modified Eagle's medium-F12에서 배양하고 유지하였다. 소혈청은 사용하기 1시간 전에 50 ℃에서 열처리하여 비활성시켜 사용하였다. HB-/ReNeo와 PB-/ReNeo/NotⅠ(+AvrⅡ) 발현벡터는 BHK 세포에 안정하게 형질전환되고, 상기에서 설명한 바와 같이 일반적인 방법(Lubin et al. (1994) Bio. Chem. 269:8639-8641)을 이용하여 제네티신(geneticin)에 대한 저항성을 가진 세포를 선별하였고, 선별된 세포는 600 ㎍/ml 제네티신을 함유한 배지에서 유지되었다. Corning T-75 플라스크에서 가득(confluent) 자란 세포를 Nunc Triple 플라스크로 옮겨 600 ㎍/ml 제네티신을 함유한 배지를 이용하여 가득 자랄 때까지 배양하였다. 가득 자라면 배지를 제거하고 혈청과 제네티신을 함유하지 않은 AIM-V 배지(Life Technologies 사)로 교체하였다. 인자 Ⅷ의 발현은 일단계 혈액응고 활성측정(one-stage coagulant activity assay, vide supra)을 수행하여 확인하였고, 배지 100-150 ml을 4 내지 5일 동안 매일 한번 수집하였다. HB-와 PB-으로 형질전환된 세포의 배양액에서 가장 높은 혈액응고 활성은 각각 102 units/ml과 10-12 units/ml로 나타났고, 이때 인자 Ⅷ가 가장 많이 발현되었음을 알 수 있다.
PB
-
의 정제
PB-을 60 % 포화된 암모니움 설페이드(ammonium sulfate)를 이용하여 배양 상층액으로부터 침전시키고, 상기에서 설명한 바와 같이 혈장유래인자 Ⅷ을 정제하기 위하여 W3-3 면역친화도 크로마토그래피(immunoaffinity chromatograph) 및 모노 Q HPLC (mono Q high pressure liquid chromatograph)을 이용하여 정제하였다 (Lollar et al. (1993) Factor Ⅷ/factor Ⅷa. Methods Enzymol. 222:128-143). PB-의특이적 혈액응고 활성도 (specific coagulant activity)는 일단계 혈액응고 분석법(Lollar et al. (1993) supra)을 이용하여 측정하였고, 이때 돼지의 혈장유래인자 Ⅷ의 혈액응고 활성도와 비슷하게 나타났다.
SDS-폴리아크릴아미드 겔 전기영동(PAGE)을 실시한 결과, 정제된 PB-는 분자량 160 kDa, 82 kDa, 76 kDa에 해당하는 부분에서 3개의 밴드를 포함하는 것으로 확인되었다. 82 kDa와 76 kDa 밴드는 A1-A2와 ap-A3-C1-C2 도메인(여기서 ap는 activation peptide를 의미함)으로 구성되는 이종이량체(heterodimer)에서 유래한 것이라는 것이 이미 알려져 있다 (Toole et al. (1984) Nature 312:342-347). 160 kDa 밴드를 폴리비닐이덴 플루오리드(polyvinylidene fluoride) 막에 옮겨 N-말단 서열을 결정하였고, 단일쇄(single chain) 인자 Ⅷ의 N-말단 서열(Toole et al. (1984) supra)로서 Arg-Ile-Xx-Xx-Tyr (Xx는 훼손(undermined)됨을 의미)을 확인하였다. 따라서, PB-에서 A2와 A3 도메인 사이에서 절단이 일어나서 프로세싱(processing)이 부분적으로 일어남을 알 수 있고, 따라서 PB-은 두가지 형태, 즉, 단일쇄(single chain) A1-A2-ap-A3-C1-C2 단백질과 A1-A2/ap-A3-C1-C2 이종이량체(heterodimer)로 구성된다. 재조합 HB-에서도 이와 비슷한 프로세싱이 보고된 바 있다 (Lind et al. (1995) Eur. J. Biochem. 232:19-27).
돼지 인자 Ⅷ의 특성분석
본 발명자들은 5' UTR의 167 bp, 신호 펩타이드 코딩부위 (57 bp), A1 (1119 bp), A3 (990 bp), C1 (456 bp) 및 C2 (483 bp)에 대응하는 돼지 fⅧ의 cDNA 서열을 결정하였다. B 도메인과 경사슬 활성화 펩타이드(light chain activation peptide) 부위 (Toole et al. (1986) supra) 및 A2 도메인(Lubin et al. (1994) supra)의 기존에 공지된 서열과 함께, 본 발명에서 보고한 서열을 통해서 돼지 fⅧ의 번역 산물에 대응하는 돼지 fⅧ의 cDNA의 서열을 완전히 결정하였다. 5' UTR 영역, 신호 펩타이드, A1 도메인 cDNA을 포함하는 단편을 5' RACE RT-PCR 방법을 이용하여 클로닝하였다. 인간 C2 서열에 기초하여 제작한 프라이머를 이용하여 수행한 RT-PCR에서 성공적으로 RT-PCR 산물을 획득하였고 결과적으로 A3, C1 도메인 및 C2 도메인의 5' 절반 정도를 클로닝하였다. C2 도메인의 3' 절반과 3' UTR cDNA를 클로닝하는 것은 어려운 것으로 확인되었다. C2 도메인의 나머지 부분은 표적 유전자 워킹(targeted gene walking) PCR 방법(Parker et al. (1991) supra)을 이용하여 클로닝하였다.
본 발명에서 보고하는 서열번호 29의 서열은 C2 도메인의 3' 말단에 위치한 nt 7045에서의 염기를 제외하고는 애매한 부분은 없다. nt 7045 위치의 염기는 상기에서 설명한 바와 같이 A 또는 G이고 이에 대응하는 코돈은 GAC (Asp) 또는 AAC (Asn)이다. 인간 및 마우스에서 이에 대응하는 코돈은 각각 GAC와 CAG (Gln)이다. 이러한 현상이 다형성(polymorphism)에 의한 것인지 PCR 반응시 부정확한 반응 때문에 일어나는 것(artifact)인지에 대해서는 알려진 바가 없다. B 도메인이 소실되고 GAC또는 AAC 코돈을 함유하는 돼지 C2 도메인을 포함하는 재조합 혼성 인간/돼지 fⅧ cDNA은 전혈액응고 활성에 큰 차이가 없는 형태로 안정하게 발현되었다. 이러한 결과를 통해서 두 개의 C2 도메인 변이체는 서로 기능면에서 차이가 없다는 것을 알 수 있었다.
Fig. 1A 내지 1H에 나타낸 바와 같이, 전장 돼지 fⅧ의 예상되는 아미노산 서열 (서열번호 30)을 번역후 변형(post-translational modification), 단백가수분해에 의한 절단 및 그 외 거대분자에 의해서 인식부위에 따라서 공지된 인간 fⅧ 서열(Wood et al. (1984) supra) 및 마우스 fⅧ 서열(Elder et al. (1993) supra)과 비교하였다. 비교된 서열에서 일치하는 정도(identity)는 표 Ⅶ에 나타낸 바와 같다. 상기에 설명한 바와 같이, 이들 종에서 B 도메인은 A 또는 C 도메인보다 다양성이 높다. 이러한 결과는 B 도메인이 분자량이 큼에도 불구하고 알려진 기능이 없다는 사실과 일치한다 (Elder et al. (1993) supra; Toole et al. (1986) supra). 본 발명의 이러한 비교결과를 통해서 돼지 fⅧ의 B 도메인은 돼지 fⅧ이 활성을 나타내는 데 필요한 부분이 아님을 증명하였다. 본 발명에서 제시한 서열 데이터를 기초로 하여, 돼지 B 도메인 전체 또는 일부분이 소실된 돼지 fⅧ 코딩 DNA를 발현시킴으로써 B 도메인 전체 또는 일부분이 소실된 돼지 fⅧ을 합성할 수 있다. 또한, A1 도메인 APC/인자 Ⅸa 절단 펩타이드(잔기 337-372) 및 경사슬 활성화 펩타이드(light chain activation peptide)에 대응하는 서열에서 다양성(divergence)이 더 높게 나타났다 (표 Ⅶ). 336 위치에서 절단하여 337-372 펩타이드를 생성하는 트롬빈의 절단자리는 마우스 fⅧ에서 Arg대신에 Glu 잔기가 있기 때문에 소실되어 있다 (Elder et al. (1993) supra). 상대적으로 빠르게 변하는(divergence) 트롬빈 절단 펩타이드 (또는 마우스 fⅧ에서 퇴화된 337-372 활성 펩타이드(activation peptide))는 기존에 피브리노펩타이드(fkbrinopeptide)로 알려진 것이다 (creighton, T. E. (1993) In Proteins: Structures and Molecular Properties, W. H. Freeman, New York, pp. 105-138). 이러한 펩타이드가 빨리 분화(divergence)하는 것은 일단 절단되면 생물학적인 기능을 잃게되기 때문일 것으로 여겨진다. fⅧ 및 fⅧa를 불활성시킬 때, 인간 fⅧ에서 Arg562는 활성화된 단백질 C에 대한 절단부위로서 더 중요한 것으로 여겨진다 (Fay, P. J. et al. (1991) j. Biol. Chem. 266:20139-20145). 이러한 절단부위는 인간 fⅧ, 마우스 fⅧ 및 돼지 fⅧ에서 보존되어 있다.
가능한 N-연결된 당질화 부위(N-linked glycosylation site, NXS/T, 여기서 X는 프롤린(proline)이 아님을 의미함)는 Fig. 1A 내지 1H에 나타낸 바와 같다. 8개의 보존된(conserved) N-연결된 당질화 부위가 있다: A1 도메인에 한 개, A2 도메인에 1개, B 도메인에 4개, A3 도메인에 1개 및 C1 도메인에 1개. A와 C 도메인에서 19개의 시스테인(cysteine)이 보존되어 있고, 반면 B 도메인에서 시스테인 잔기들은 상이(divergence)하게 나타났다. fⅧ에서 7개의 황결합(disulfide linkage) 중 6개가 인자 Ⅴ와 세룰로플라스민(ceruloplasmin)와 동일한 위치에서 나타났고, C 도메인의 황결합은 인자 Ⅴ에서도 발견되었다 (McMullen, B.A. et al. (1995) Protein Sci. 4:740-746). 인간 fⅧ은 346, 718, 719, 723, 1664, 1680 위치에서 설페이트화된티로신(sulfated tyrosine)을 포함한다 (Pittman, D.D. et al (1992) Biochemistry 31:3315-3325; Michnick, D.A. et al (1994) J. Biol. Chem. 269:20095-20102). CLUSTALW 프로그램을 이용하여 인간 fⅧ에 있는 Tyr346에 대응하는 마우스 타이로신(Tyrosine)을 비교하지는 못했지만, 이러한 잔기는 마우스 fⅧ 및 돼지 fⅧ에서 보존되어 있다 (Fig. 1).
마우스 및 돼지 혈장을 이용하여 혈우병 A 환자의 혈장에서의 혈액응고 결함을 치료할 수 있고, 이러한 사실은 이들 종의 A 및 C 도메인에서 아미노산 잔기의 보존수준과 일치하는 것이다. 돼지 fⅧ의 전혈액응고 활성(procoagulant activity)은 인간 fⅧ보다 높다 (Lollar, P. et al. (1992) J. Biol. Chem. 267:23652-23657). 또한, 본 발명에서 설명한 바와 같이 발현시켜 정제한 재조합 돼지 인자 Ⅷ(B 도메인이 소실된 것임)은 인간 fⅧ보다 더 높은 혈액응고 활성(specific coagulant activity)을 나타냈고, 이러한 활성도는 혈장에서 유래한 돼지 fⅧ와 비슷한 수준이었다. 이와 같은 높은 활성은 활성화된 A1/A2/A3-C1-C2 fⅧ 이종이량체(heterodimer)에서 A2 서브단위가 자발적으로 해리되는 속도를 저하시켰기 때문에 나타난 결과이다. 종간 전혈액응고 활성도에서 차이가 나는 것은 진화과정중에 각 종이 적응하면서 나타난 변화에 의한 것인지는 아직 알려진 바가 없다 (Perutz, M.F. (1996) Adv. Protein Chem. 36:213-244). 이제 번역된 산물과 대응하는 돼지 fⅧ cDNA의 서열은 완변하게 확보되었고, 동종주사 돌연변이(homolog scanning mutagenesis) (Cunningham, B.C., et al. (1989) Science 243:1330-1336)을 이용하여 인간 fⅧ과 더 우수한 혈액응고 활성을 보이는 돼지 fⅧ 사이에 구조적 차이점을 밝힐 수 있다.
돼지 fⅧ은 전형적으로 fⅧ을 투여받은 혈우병 환자에서 발견되는 또는 자가항체로서 자연적으로 발생하는 억제성 항체(inhibitory antibody)와 반응성이 낮다. 이러한 현상 때문에 억제성 항체를 가진 환자를 치료할 경우 돼지 돼지 fⅧ 농축물(concentrate)을 사용한다 (Hay and Lozier (1995) supra). 대부분의 억제인자(inhibitor)는 A2 도메인 또는 C2 도메인에 있는 에피토프와 상호작용을 한다 (Fulcher, C.A. et al. (1985) Proc. Natl. Acad. Sci. USA 82:7728-7732; Scandella, D. et al. (1988) Proc. Natl. Acad. Sci. USA 85:6152-6156; Scandella, D. et al. (1989) Blood 74:1618-1626). 또한, 생물학적으로 중요성이 알려지지 않은 에피토프가 A3 또는 C1 도메인에서 확인되었다 (Scandella, D. et al. (1989) supra; Scandella, D. et al. (1982) Blood 82:1767-1775; Nakai, H. et al. (1994) Blood 84:224a). A2 에피토프는 동종주사 돌연변이(homolog scanning mutagenesis)에 의해서 484 내지 508까지의 잔기로 구성된다 (Healey et al. (1995) supra). 이러한 25 잔기로 구성된 부분은 서열비교시 상대적으로 낮은 일치성(indentity)(16/25 또는 64%)을 보였다. 항체가 결합하면 활성이 억제되어 기능적으로 중요하게 작용하는 이러한 부분이 상대적으로 좀 더 빠르게 변이한다는 것은 매우 흥미로운 사실이다. 돼지 A2 도메인 및 A3 도메인을 서로 비교한 경우, A2 에피토프와 A3 도메인의 이에 대응하는 영역 사이에 상동성(homology)은 관찰되지 않았다.
인간 fⅧ의 C2 에피토프는 소실 맵핑(deletion mapping)을 통해서 잔기 2248-2312에 존재하는 것으로 제안되었다 (Scandella, D. et al. (1995) Blood 86: 1811-1819). 이러한 65개 잔기로 구성된 부분에서 인간 및 돼지 fⅧ는 83 %의 일치성(identity)을 가진다. 그러나, C2 에피토프를 밝히기 위해 동종주사 돌연변이(homolog scanning mutagenesis)을 수행한 결과, 기대했던 것과는 다르게 C2 도메인의 주요 결정인자(determinant)는 인간 fⅧ의 아미노산 잔지 2181-2243 (서열번호 2)에 대응하는 부분에 위치하는 것으로 밝혀졌다 (Fig. 1H).
혼성 인간/돼지 인자 Ⅷ 단백질은 본 발명에서 설명한 대로(실시예 5) 인간 인자 Ⅷ의 C2 도메인의 다양한 부분을 돼지 인자 Ⅷ의 이에 대응하는 부분으로 치환하여 합성된 것이다. 다양한 C2-혼성 인자 Ⅷ의 합성은 서열번호 30에서 나타낸 바와 같은 돼지 C2 부분을 인코딩하는 뉴클레오타이드 서열을 이용하여 혼성을 코딩하는 DNA을 제조함으로써 달성되었다. 각 혼성 DNA를 형질전환된 세포에서 발현시키고, 배양배지에서 발현된 혼성 인자 Ⅷ을 부분적으로 정제하였다. 억제인자가 없는 조건하에서 혈액응고 활성을 일단계 혈액응고 분석법(one-stage clotting assay)을 이용하여 측정하였다.
5개의 인간 억제인자을 각 혼성 인자 Ⅷ의 활성을 검사하는 데 사용하였다. 재조합 인간 C2 도메인의 억제를 중화시키는 능력이 있다는 사실에 기초하여, 안티 인자 Ⅷ(anti factor Ⅷ)을 함유하는 억제인자 혈장(inhibitor plasma)을 이용하여 인간 C2 도메인에 대해서 직접 실시하였다. 모든 혈장에서, 억제인자 역가는 C2 도메인 또는 경사슬(light chain)에 의해서 79 % 이상 중성화되었고, 재조합 인간 A2 도메인에 의해서는 10 % 이하로 중성화되었다. 또한, C2-혼성 인자 Ⅷ을 C2 도메인에 결합하는 마우스 단일클론항체 (murine monoclonal antibody) 또는 인간 C2 억제성 항체와 반응시킨 결과, 인지질과 폰 빌레브란트 인자(von Willebrand factor, vWF)에 인자 Ⅷ의 결합이 억제되었다.
C2-혼성 인자 Ⅷ에 대한 억제인자의 역가를 비교했을 때, 인간 C2 억제인자 에피토프의 주요 결정인자(determinant)는 잔기 2181-2243 (서열번호 2, Fig. 1H)에 위치하는 것으로 밝혀졌다. 잔기 2253에서 C-말단에 결합하는 안티-C2 항체 (anti-C2 antibody)는 4 또는 5 환자 혈청에서 확인되지 않았다. 인간 아미노산 잔기 2181-2199 및 2207-2243에 대응하는 돼지 서열을 포함하는 혼성체들(hybrids)을 비교하였을 경우, 이 두 부분에서 항체 결합이 일어난다는 것이 밝혀졌다. 인간 잔기 2181-2243에 대응하는 돼지 아미노산 서열은 서열번호 30에 나타낸 바와 같이 번호 1982-2044로 표기하였다. 돼지 아미노산 서열 1982-2044을 인코딩하는 돼지 DNA의 서열은 서열번호 29에 나타낸 바와 같이 nt 5944-6132 번호로 나타냈다.
Fig. 1H에 나타낸 바와 같이, 2181-2243 부분에서 인간과 돼지 서열사이에 16개의 아미노산이 다르게 나타났다. 이러한 차이는 잔기 2181, 2182, 2195-2197, 2199, 2207, 2216, 2222, 2224-2227, 2234, 2238, 2243에서 나타났다. 이러한 위치에서 아미노산을 치환하여 인간 안티-C2 억제성 항체에 대해 반응성이 없는 변형된 인간 인자 Ⅷ을 합성할 수 있다. 알라닌 주사 돌연변이(alanine scanning mutagenesis)을 통해서 상기에 설명한 위치에 있는 원래의 잔기를 알라닌으로 쉽게 치환할 수 있다. 또한, 알라닌 외에 다른 아미노산이 사용될 수 있다. 인간과 돼지, 또는 인간과 마우스간에 동일하지 않은 아미노산, 또는 항체의 결합을 가장 용이하게 하는 아미노산을 알라닌으로 치환하면, 억제성 항체에 대해서 반응성이 감소된 변형된 인자 Ⅷ을 생산할 수 있다.
Figs. 1A 내지 1H은 인간, 돼지, 마우스의 인자 Ⅷ의 아미노산 서열을 서로 비교한 결과를 보여준다. Fig. 1A는 신호 펩타이드 부위 (인간, 서열번호 31; 돼지, 서열번호 30 및 아미노산 1-19; 마우스, 서열번호 28 및 아미노산 1-19)을 비교한 것이다. Fig. 1A 내지 1H에 나타낸 아미노산의 번호는 성숙 단백질(mature protein)에서 나타나는 첫 번째 아미노산인 알라닌(alanine)을 1번으로 하여 표기하였고, 여기서 신호 펩타이드는 음의 정수로 표기하였다. 또한, 서열번호 2에 나타낸 바와 같은 인간 fⅧ의 서열에서도 첫 번째 아미노산인 알라닌(alanine)을 1번으로 하여 표기하였다. 서열번호 28에 나타낸 마우스 fⅧ 및 서열번호 30에 나타낸 돼지 fⅧ 아미노산 서열에서 첫 번째 아미노산인 알라닌(alanine)을 20번으로 하여 표기하였다. 인간, 돼지, 마우스 fⅧ의 서열을 비교하여 보여주는 Fig. 1A 내지 1H에서, 아미노산 일치성(identity)가 가장 높게 나타난 영역을 나란히 배열하였다. Fig. 1A 내지 1H에서 사용한 아미노산 번호는 인간 fⅧ의 경우에만 그대로 적용하였다. Fig. 1B는 인간의 A1 도메인 (서열번호 2, 아미노산 1-372), 돼지 A1 도메인 (서열번호 30, 아미노산 29-391), 마우스 A1 도메인(murine)(서열번호 28, 아미노산 20-391)에 대한 아미노산 서열을 보여주고 있다. Fig. C는 인간(서열번호 2, 아미노산 373-740), 돼지(서열번호 30, 아미노산 392-759), 마우스(서열번호 28, 아미노산 392-759)에서 유래한 인자 Ⅷ A2 도메인에 대한 아미노산 서열을 보여주고 있다. Fig. D는 인간(서열번호 2, 아미노산 741-1648), 돼지(서열번호 30, 아미노산 760-1449), 마우스(서열번호 28, 아미노산 760-1640)에서 유래한 인자 Ⅷ B 도메인에 대한 아미노산 서열을 보여주고 있다. Fig. E는 인간, 돼지, 마우스에서 유래한 인자 Ⅷ 경사슬 활성화 펩타이드(light chain activation peptide)에 대한 아미노산 서열을 비교한 결과를 보여주고 있다 (각각, 서열번호 2, 아미노산 1649-1689; 서열번호 30, 아미노산 1450-1490; 서열번호 28, 아미노산 1641-1678). Fig. F는 인간, 돼지, 마우스에서 유래한 인자 Ⅷ A3 도메인에 대한 아미노산 서열을 비교한 결과를 보여주고 있다 (각각, 서열번호 2, 아미노산 1690-2019; 서열번호 30, 아미노산 1491-1820; 서열번호 28, 아미노산 1679-2006). Fig. G는 인간, 돼지, 마우스에서 유래한 인자 C1 도메인에 대한 아미노산 서열을 비교한 결과를 보여주고 있다 (각각, 서열번호 2, 아미노산 2020-2172; 서열번호 30, 아미노산 1821-1973; 서열번호 28, 아미노산 2007-2159). Fig. H는 인간, 돼지, 마우스에서 유래한 인자 C2 도메인에 대한 아미노산 서열을 비교한 결과를 보여주고 있다 (각각, 서열번호 2, 아미노산 21730-2332; 서열번호 30, 아미노산 1974-2133; 서열번호 28, 아미노산 2160-2319).
다이아몬드 표시는 타이로신 설페이트 부위(tyrosine sulfated site)을 나타내고, 인자 Ⅸa, 인지질, 단백질 C에 대한 결합부위는 두줄로 표시하였고, 안티-A2 및 안티-C2 억제성 항체에 대한 결합부위는 이탤릭체로 나타냈다. 별표는 보존된 염기서열을 나타낸다. 또한 서열번호 29는 돼지 인자 Ⅷ cDNA, 서열번호 30은 돼지 인자 Ⅷ의 예측한 아미노산 서열을 나타낸다. 인간 인자 Ⅷ에서 번호는 문헌을 참고하여 결정하였다 (Wood et al. (1984) supra). A1, A2, B 도메인은 372와 740 위치에서 트롬빈 절단 부위 및 1648위치에 있는 알려지지 않은 단백질 분해효소(protease) 절단 부위에 따라서 정의된 것이고, 각각 잔기 1-372, 373-740, 741-1648에 해당하는 서열을 갖는다 (Eaton, D.L. et al. (1985) Biochemistry 25:8343-8347). A3, C1, C2 도메인은 각각 잔기 1690-2019, 2020-2172, 2173-2332의 서열을 갖는다 (Vehar et al. (1984) supra). 트롬빈 (인자 Ⅱa), 인자 Ⅸa, 인자 Ⅹa 및 APC 의 절단 부위(cleavage site) (Fay et al. (1991) supra; Eaton, D. et al. (1986) Biochemistry 25:505-512; Lamphear, B.J. et al. (1992) blood 80:3120-3128)는 이들이 반응하는 아기닌(arginine) 위에 효소이름을 적어 표시하였다. 산성 펩타이드는 트롬빈 또는Ⅹa가 인자 fⅧ 경사슬의 1689 위치에 작용했을 때 절단된 것이다. 인자 Ⅸa(Fay, P.J. et al. (1994) J. Biol. Chem. 269:20522-20537; Lenting, P.J. et al. (1994) J. Biol. Chem. 269:7150-7155), 인지질 (Foster, P.A. et al. (1990) blood 75:1999-2004), 단백질 C (Walker, F.J. et al. (1990) J. Biol. Chem. 265:1484-1489)에 대한 결합 부위는 두줄로 밑줄쳐 나타냈다. 안티-A2 억제성 항체대한 기존에 알려진 결합부위는 이탤릭체로 표시하였다. 본 발명에서 밝힌 C2 억제인자 에피토프(인간 아미노산 2181-2243)는 Fig. 1H에서 한줄로 밑줄쳐 나타냈다. 타이로신 설페이트 부위 (tyrosine sulfation site) (Pittman et al. (1992) supra; Michnick et al. (1994) supra)는 다이아몬드 모양으로 표시하였다.
[실시예 7] POL1212의 제조 및 BHKC(baby hamster kidney cells)에서의 발현
POL1212는 B 도메인의 일부분이 소실된 돼지 fⅧ로서, B 도메인의 N-말단의 12개의 아미노산과 C-말단의 12개의 아미노산을 그대로 가지고 있다.
돼지 fⅧ의 A1, A2, ap-A3-C1 및 C2 도메인에 대한 서열을 인코딩하는 cDNA는 실시예 5에서 설명한 바와 같이 획득하였다. DNA 뉴클레오타이드 서열 및 돼지 인자 Ⅷ의 아미노산 서열은 각각 서열번호 29와 30에 나타낸 바와 같다. 증폭된 단편들을 플라스미드 pBluescriptⅡ KS(-)(pBS)에 각각 클로닝하였다.
POL1212는 B 도메인의 대부분이 소실된 돼지 fⅧ을 인코딩하는 cDNA을 의미하는 것으로 A2 와 ap 도메인 사이에 24개 아미노산으로 구성된 링커(linker)을 인코딩하는 DNA 서열을 포함하고 있다. POL1212를 포유세포용 발현벡터 ReNeo(Biogen 사)에 삽입하였다. ReNeo 발현벡터는 박테리아에서 자가복제할 수 있고 인자 Ⅷ의 일시적 발현(transient expression)에 사용되는 COS 세포에서 에피솜(episome)으로 복제할 수 있거나 다양한 포유세포내로 안정하게 삽입될 수 있다. POL1212는 1) 복제 오리진(origin)과 앰피실린 저항성 유전자를 포함하여 플라스미드 pBR322에서 유래한 서열, 2) SV40 프로모터/인핸서(enhancer), SV40 소 t 인트론(small t intron) 및 SV40 폴리아데닐레이션 신호 조절 요소(polyadenylation signal regulatory element)의 조절하에 있는 네오마이신(neomycin) 저항성 유전자, 3) SV40 인핸서, 아데노바이러스 타입 2 주요 후기 프로모터(major late promoter) 및 아데노바이러스 타입 2 삼부의 리더 서열(tripartite leader sequence)의 조절하에서 발현되는 fⅧ과 이의 신호 펩타이드에 대한 삽입부위을 포함한다. 이와 비슷한 기능의 성분을 포함하는 벡터는 ReNeo 발현벡터 대신에 사용될 수 있다.
POL1212/ReNeo 발현벡터는 몇 단계에 걸쳐서 제조되었다. 먼저, 돼지 fⅧ 중사슬(heavy chain, A1-A2)을 인코딩하는 cDNA와 돼지 fⅧ 경사슬(light chain, ap-A3-C1-C2)을 인코딩하는 cDNA을 각각 pBS에 삽입하였다. 이들 벡터로부터 B 도메인이 소실된 돼지 fⅧ을 인코딩하는 DNA을 pBS에 삽입하였다 (PB-/pBS). 이러한 벡터는 인간 fⅧ(인간 nt 2278-5001)에서 잔기 741-1648과 대응하는 아미노산으로 정의되는 B 도메인 전체가 소실되어 있다. 다음으로, B 도메인이 소실된 인간fⅧ 발현벡터 ReNeo (HB-/ReNeo)에서 인간 A2 도메인을 돼지 A2 도메인을 인코딩하는 DNA로 치환하였다. 돼지 중사슬/pBS와 PB-/pBS 벡터을 사용하여 두 단계에 걸쳐서 인간 도메인을 돼지 중사슬의 나머지 부분을 인코딩하는 DNA과 돼지 경사슬을 인코딩하는 DNA로 치환하였다. C-말단 5개 아미노산과 N-말단 9개 아미노산을 인코딩하는 인간 B 도메인 단편은 A2와 A3 도메인 사이에 삽입시키고 결과 제조된 벡터를 PSQ/ReNeo라고 명명하였다 (Healey et al. (1998) 92:3701-3709). 잔기 Glu2181-Val2243은 인간 인자 Ⅷ의 C2 도메인에 존재하는 억제성 에피토프의 주요 결정인자(determinant)를 포함한다. 이러한 벡터는 C-말단 12개 아미노산과 N-말단 12개 아미노산을 인코딩하는 돼지 B 도메인 단편을 제조할 때 주형으로 사용되었다. 이 단편을 A2와 A3 도메인사이에 삽입시킴으로써 최종 벡터인 POL1212/ReNeo을 제조하였다.
POL1212의 24개 아미노산으로 구성된 링커(linker)은 돼지 fⅧ B 도메인의 C-말단 12개 아미노산과 N-말단 12개 아미노산으로 구성된된다. POL1212 링커는 다음과 같은 서열을 갖는다.
SFAQNSRPPSASAPKPPVLRRHQR (서열번호 32)
1212 링커에 대응하는 뉴클레오타이드 서열 및 이의 주변 아미노산은:
(서열번호 33)
GTC ATT GAA CCT AGG AGC TTT GCC CAG AAT TCA AGA
V I E P R S F A Q N S R
CCC CCT AGT GCG AGC GCT CCA AAG CCT CCG GTC CTG
P P S A S A P K P P V L
CGA CGG CAT CAG AGG GAC ATA AGC CTT CCT ACT
R R H Q R D I S L P T
POL1212 링커는 SOE 돌연변이(splicing-by-overlap extension mutagenesis)을 다음과 같이 수행하여 합성하였다.
SOE 산물을 생산하기 수행한 PCR 반응은 다음과 같다.
반응 1
바깥쪽 프라이머 (outside primer): Rev 4, 서열번호 29에서 nt 1742-1761으로 이루어진 돼지 A2 프라이머이고, 서열은 5'-GAG GAA AAC CAG ATG ATG TCA-3' (서열번호 34)이다.
안쪽 프라이머 (inside primer): OL12, OL1212의 5' 말단의 15개 아미노산 및 돼지 A2 의 3' 말단의 5개 아미노산에 대한 돼지 역 프라이머(reverse primer)이고, 서열은 5'-CTT TGG AGC GCT CGC ACT AGG GGG TCT TGA ATT CTG GGC AAA GCT CCT AGG TTC AAT GAC-3' (서열번호 35)이다.
주형: PSQ/ReNeo
산물: A2 도메인에서 nt 1742에서부터 OL1212에서 nt 2322까지의 돼지 DNA, 580 bp
반응 2
바깥쪽 프라이머 (outside primer): P2949, 서열번호 29에서 nt 2998-3021으로 이루어진 돼지 역(reverse) A2 프라이머이고, 서열은 5'-GGT CAC TTG TCT ACC GTG AGC AGC-3' (서열번호 29)이다.
안쪽 프라이머 (inside primer): OL12+, 서열번호 29에서 nt 2302-2367으로 이루어진 OL1212의 5' 말단의 6개 아미노산 및 돼지 A2 의 3' 말단의 16개 아미노산에 대한 돼지 프라이머이고, 서열은 5'-CCT AGT GCG AGC GCT CCA AAG CCT CCG GTC CTG CGA CGG CAT CAG AGG GAC ATA AGC CTT CCT ACT-3' (서열번호 36)이다.
주형: PSQ/ReNeo_
산물: OL1212에서 nt 2302에서부터 A3 도메인에서 nt 3021까지의 돼지 DNA, 719 bp
SOE 반응
프라이머: Rev 4, P2949-
주형: 반응 1에서 획득한 단편 및 반응 2에서 획득한 단편(low melt)
산물: A2 도메인에서 nt 1742에서부터 A3 도메인에서 nt 3021까지의 돼지 DNA, 1279 bp, 반응산물은 에탄올 침전시켰다.
1212 링커(linker)는 SOE 산물(인서트)과 PSQ/ReNeo 벡터을 BsaBⅠ으로 자른 후에 PSQ/ReNeo 벡터에 삽입하였다. 벡터와 인서트(insert)는 T4 리가제(ligase)를 이용하여 연결하였고, 생성된 벡터으로 E. coli XL 1-Blue 세포을 형질전환시켰다. 몇 개의 콜로니를 선택해서 플라스미드 DNA를 정제하고 1212 링커 및 다른 PCR에 의해서 증폭된 서열에 대한 DNA 서열을 분석하였다.
BHK (baby hamster kidney) CRL-1632 세포의 배양
BHK 세포주는 ATCC에서 구입(accession identifiction CRL-1632)하여 사용할 때까지 -20 ℃에 동결된 상태로 저장하였다. 사용하고자 할 때는 37 ℃에서 녹인 후 완전 배지 (DMEM/F12, 50 U/ml 페니실린, 50 ㎍/ml 스트렙토마이신, 10 % FBS) 10 ml에서 배양하였다. FBS는 Hyclone 사(Logan Utah)에서 구입하였다. 배양후 세포는 300 rpm에서 2분동안 원심분리하여 수거하였다. 배지는 흡입에 의해서 제거하였고 세포는 2ml의 완전 배지에 다시 현탁하여 20 ml의 완전 배지가 들어있는 T-75 플라스크에 넣어서 배양하였다.
POL1212는 BHK(baby hamster kidney)와 CHO(chinese hamster ovary) 세포에서 발현시켰다. 두 개의 BHK 세포주, 즉 ATCC에서 구입한 CRL-1632 세포주와 British Columbia 주립대학의 R. Mcgillivray에게서 구입한 BHK 세포주(Funk, et al. (1990) Biochemistry 29:1654-1660)를 사용하였다. 후자의 세포주는 본 발명자가 속한 실험실에서 선택과정없이 계대배양하였고 BHK1632(Emory)로 표시하여 사용하였다. CHO 세포주로서 CHO-K1(ATCC accession number CCL-61)을 사용하였다. 발색측정법(chromogenic assay)을 이용하여 활성을 측정하였을 때, Emory 세포주와 CHO-K1세포주을 이용하여 확보한 클론에서 발현율이 CRL-1632을 이용하여 확보한 클론에서 보다 더 높게 나타났다.
T-75 플라스크에서 세포는 한층(monolayer)을 형성하면서 가득(confluent) 자란다. POL1212/ReNeo 플라스미드를 함유하는 E. coli XL 1-Blue 세포를 LB/앰피실린(50 mg/ml) 배지에서 배양한 배양액 60 ml을 준비하였다.
POL1212/ReNeo 벡터을 이용한 CRL-1632 BHK 세포의 형질전환
밤새 배양한 POL1212/ReNeo XL 1-Blue 세포에서 CA Spin Miniprep kit (Qiagen, Valencia, CA)을 이용하여 DNA를 정제하였다. 하나의 플라스크에 배양된CRL-1632 세포 총 2 ml에서 0.2 ml은 저장을 위해서 한 플라스크에서 배양하였고, 0.3 ml은 형질전환을 수행하기 위하여 한 플라스크에 넣어 배양하였다. 그 외 플라스크는 새로운 배지로 교체해 주었다. 세포는 DMEM/F12, 10 % Hyclone FBS, 50 U/ml 페니실린, 50 ㎍/ml 스트렙토마이신을 포함하는 배지에서 배양하였다. 형질전환(transfection) 실험을 실시하기 위하여, T-75 플라스크에서 배양한 CRL-1632 세포을 1:5000 Versene 2 ml를 이용하여 떼어낸 후 이중 0.3 ml을 새로운 배지(DMEM/F12, 10 % Hyclone FBS, 50 U/ml 페니실린, 50 ㎍/ml 스트렙토마이신)를 사용하여 6-웰 플레이트에 분주하여 50-90 %까지 자랄 때까지 배양하였다.
하기의 용액은 멸균된 1-2 ml 테스트 튜브에서 준비하였다.
A) Miniprep kit을 이용하여 정제한 POL1212/ReNeo 48 ㎕ (10 ㎍) + 혈청(serum)이 함유되지 않은 배지 (DMEM/F12) + 리포펙틴(LipofectinTM)(Life Technologies, Gaithersburg, MD) 10 ㎕
B) 리포펙틴(LipofectinTM) 10 ㎕ + 배지 190 ㎕(mock 형질전환)
A) 또는 B)을 잘 혼합하여 실온(RT)에서 15동안 배양하여 DNA와 리포펙틴이 서로 반응하도록 하였다. 이동안에 세포를 DMEM/F12 2 ml로 2번 워싱(washing)하였고 1.8 ml의 DMEM/F12을 다시 첨가하였다. DNA/리포펙틴 복합체을 포함하는 반응액을 세포위에 한 방울씩 떨어뜨리면서 첨가한 후 조심해서 돌려주면서 혼합하였다. 세포를 배양기안에서 밤새 배양시킨 후, DNA/리포펙틴을 제거하고 혈청이 포함된 배지로 갈아 주었다. 30-48 시간 더 배양한 후, 1:20, 1:50, 1:100, 1:250, 1:500으로 희석하여 10 cm 배양접시에 옮겨 535 ㎍/ml의 제네티신(Life Technologies, Gaithersburg, MD)이 함유된 배지(+혈청) 10 ml를 넣어서 배양하였다. 다음 몇 일 동안, POL1212/ReNeo 플라스미드로 형질전환되지 않은 세포는 제네티신 존재하에서 죽게되고, 살아남은 세포는 계속 복제하여 육안으로 확인가능한 크기로 한층(monolayer)의 콜로니를 형성한다.
CRL-1632 BHK 세포에서 POL1212의 발현 및 분석
원통형 모양의 작은 플라스틱 링을 콜로니 주변에 놓고 완전 배지을 이용하여 흡입한 후 테스트 튜브로 옮긴다. 이와 같이 분리된 콜로니는 링 클로닝 콜로니(ring cloned colony)로 언급되고, 24 웰 플레이트에 각각 플레이팅하여 완전배지에서 배양하였다.
발색기질측정법(chromogenic substrate assay)을 이용한 형질전환된 CRL-1632 BHK 세포에서 인자 Ⅷ의 발현확인
세포배양시 상층액에서 유래한 POL1212 샘플을 정제된 돼지 인자 Ⅸa, 0.05 mM 50 nM 포스파티딜세린-포스파지딜콜린(PCPS) 소포 (phosphatidylserine-phosphatidylcholine vesicles)을 함유하는 0.15 M NaCl, 20 mM HEPES, 5 mM CaCl2, 0.01 % Tween-80으로 구성된 용액 (pH 7.4)과 함께 혼합하였다. 대조구로서, 세포 배양배지를 형질전환(mock transfection)에 사용하였다. 트롬빈과 인자 Ⅹ를 각각 40 nM, 425 nM의 최종 농도로 동시에 첨가하였다. 트롬빈은 PCPS와 함께 인자 Ⅷ을 활성화시키고, 인자 Ⅹ가 활성화되는 동안 인자 Ⅸa에 대한 조효소(cofactor)로서 작용한다.
5분 후, EDTA을 50 mM의 최종농도로 첨가하여 인자 Ⅸa/인자 Ⅷa/PCPS의 작용에 의한 인자 Ⅹ의 활성화를 종결시킨다. 동시에 트롬빈 억제제인 재조합 데설라토히루딘(recombinant desulfatohirudin)을 100 nM의 최종농도로 첨가함으로써 트롬빈에 의한 인자 Ⅷ의 활성화를 종결시킨다. 반응혼합물에서 25 ㎕을 취하여 스펙트로자임(Spectrozyme) Ⅹa (America Diagnostica, Greenwich, CT)을 함유하는 미량역가판(microtiter plate)의 웰에 옮긴다. 여기서 스펙트로자임(Spectrozyme) Ⅹa은 발색측정(chromogenic assay)시 인자 Ⅹa에 대한 기질로서 사용되고, 0.6 mM의 최종농도로 사용되었다. 인자 Ⅹa에 의해서 스펙트로자임(Spectrozyme) Ⅹa이 절단되므로, 405 nm에서 흡광도는 Vmax Kinetic Plate Reader (Molecular Devices, Inc., Menlo park, CA)을 이용하여 5분 동안 연속적으로 측정한다. 결과는 A405/min으로 표시하였다.
10개의 링 클로닝 콜로니(ring-cloned colony)의 인자 Ⅷ에 대한 발색측정(chromogenic assay)
| 콜로니 수 | A405/min (x103) |
| 버퍼 | 0.2 |
| 1 | 2.1 |
| 2 | 8.4 |
| 3 | 6.4 |
| 4 | 10.7 |
| 5 | 12.5 |
| 6 | 7.6 |
| 7 | 51.3 |
| 8 | 139.5 |
| 9 | 3.8 |
| 10 | 8.4 |
이러한 결과에서 알 수 있듯이, 10개 콜로니 모두에서 대조구보다 적어도 10배 이상 높은 인자 Ⅷ 활성도을 나타냈다.
콜로니 8이 가장 높은 활성도를 나타냈고, 따라서 콜로니 8의 배지의 인자 Ⅷ 혈액응고활성에 대해서 일단계 활성 분석법을 이용하여 좀 더 조사하였다. 인자 Ⅷ이 결핍된 혈장 (George King Biomedical Overland Park, KA) 50 ml, 샘플 또는 표준 시료 5 ml을 활성화된 부분 트롬보플라스틴 시약(activated partial thromboplastin time(APTT) reagent, Organon Teknika, Durham, NC) 50 ml과 함께 37 ℃에서 3분 동안 배양하였다. 콜로니 8의 배지는 0.15 M NaCl와 0.02 M HEPES로 구성된 버퍼용액 (pH 7.4)에 희석하여 사용하였고, 여기서 대조구로서 완전 배지를 사용하였다. 50 ml의 20 mM CaCl2을 첨가하여 혈액응고를 유발하였다. 혈액응고 시간 (clotting time)은 ST4 BIO 혈액응고 기구(Coagulation Instrument) (Diagnostica Stago, Parsippany, NJ)을 이용하여 측정하였다. 표준곡선은 시트레이트가 첨가된 정상인의 혈장 lot 0641 (George King Biomedical, Overland Park, KA)을 희석시킨 것을 사용하여 얻었다. 표준으로 사용된 인자 Ⅷ 농도는 0.9 units/ml이었다.
표준곡선
희석
U/ml
혈액응고 시간
1) 희석 안함 0.96 45.2
2) 1/3 (HBS) 0.32 53.7
3) 1/11 (HBS) 0.087 62.5
4) 1/21 (HBS) 0.046 68.9
혈액응고 시간 대 표준 농도의 로그값의 선형회귀분석에서(linear regression)에서 상관계수는 0.997이었다.
테스트 시료의 혈액응고 시간은 다음과 같고, 표준곡선을 이용하여 units/ml으로 전환하였다.
샘플
혈액응고시간 (초)
Units/ml
1) 콜로니 8 (24hr), 1/10 in HBS 40.6 1.74x10=17.4
2) 콜로니 8 (24hr), 1/10 in HBS 41.1 1.63x10=16.3
3) 콜로니 8 (24hr), 1/20 in HBS 47.7 0.69x20=13.8
4) 콜로니 8 (24hr), 1/20 in HBS 47.2 0.73x20=14.6
5) 완전 배지 82.9 0.007
6) 완전 배지 83.3 0.006
이러한 결과에서 콜로니 8의 혈액응고활성은 대조구보다 약 2000배 더 높게 나타났다.
POL1212를 인코딩하는 DNA 서열은 서열번호 37에 나타낸 바와 같다. POL1212의 아미노산 서열은 서열번호 38에 나타낸 바와 같다. 면역친화도 크로마토그래피(immunoaffinity chromatography), HPLC 크로마토그래피와 같은 알려진 방법을 이용하여 POL1212를 더욱 정제하였다 (참고, 실시예 2와 3).
마치는 말
POL1212와 관련된 서열을 인코딩하는 DNA 및 아미노산 서열에 기능에 중요한 부분에 영향을 주지 않으면서 약간의 변형이 도입될 수 있다는 것은 이해되어야 한다. 예를 들면, A2 도메인과 활성화 펩타이드(activation peptide)사이에 링커(linker)을 포함하는 B 도메인 서열의 길이는 본 발명이 속하는 기술분야에서 알려진 범위내에서 증가되거나 감소될 수 있다. 본 발명에서 설명한 POL1212 및 B 도메인이 소실된 돼지 인자 Ⅷ에 의해서 제공되는 기능 및 본 발명이 속하는 기술분야에서 알려진 기능을 유지하면서, 링커 부분의 서열을 변화시킬 수 있다. 사람의 혈액에서 혈액응고 활성을 갖는 인자 Ⅷ의 알려진 아미노산 서열을 기초로 하여, POL1212의 기능은 그대로 유지하면서 POL1212의 기본적인 아미노산 서열에서 각 아미노산 또는 펩타이드 단편이 기능이 알려진 변이체로 치환될 수 있다. 이러한 변이형태는 여기서 언급한 것에 한정되지 않고 다만 단백질의 기능에 중요한 부분을 실질적으로 변형시키지 않으면서 본 발명이 속하는 기술분야의 당업자에 의해서 실시될 수 있는 서열변형에 대한 예시일 뿐이다. 따라서 모든 다양한 변이 및 변형이 본 발명에서 청구한 범위 및 등가 범위 내에서 실시될 수 있음은 당연한 것이다.
서열 번호 목록
서열번호
특성
1 인간 인자 Ⅷ cDNA, 성숙 단백질에서 아미노산 1번에 대한 코 돈은 뉴클레오타이드 208번에서 시작한다.
2 인간 인자 Ⅷ 아미노산 서열
3 돼지 인자 Ⅷ A2 도메인 cDNA
4 돼지 인자 Ⅷ A2 도메인 아미노산 서열
5-27 올리고뉴클레오타이드 프라이머 서열 (실시예 5)
28 마우스 인자 아미노산 서열
29 돼지 인자 Ⅷ cDNA
30 돼지 인자 Ⅷ 아미노산 서열
31 인간 인자 Ⅷ 신호 펩타이드 아미노산 서열
32-36 올리고뉴클레오타이드 프라이머 서열 (실시예 7)
37 POL1212 코딩 DNA
38 POL1212 아미노산 서열
관련출원 상호참조
본 출원은 1998년 3월 10일자로 출원된 미국특허 출원번호 제 09/037,601호를 우선권으로 주장하고 있으며, 상기 출원된 미국특허는 1996년 6월 26일자로 출원된 미국특허 출원번호 제 08/670,707호 및 1997년 6월 26일자로 출원된 국제특허 출원번호 제 PCT/US97/11155의 일부계속출원이며, 상기 미국특허 출원번호 제 08/670,707호는 미국특허 제 5,859,204호로 등록되었다.
미연방정부의 연구지원
본 발명은 미국립보건원(NIH)의 연구비를 부분적으로 지원 받아 연구한 결과이며, 따라서 미연방정부는 본 발명에 대한 권리를 갖는다.
SEQUENCE LISTING
<110> Emory University
<120> MODIFIED FACTOR VIII
<130> 75-95I WO
<140> PCT/US01/05076
<141> 2001-02-16
<150> US 09/523,656
<151> 2000-03-10
<150> US 09/037,601
<151> 1998-03-10
<150> US 08/670,707
<151> 1996-06-26
<160> 38
<170> PatentIn Ver. 2.0
<210> 1
<211> 9009
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (208)..(7203)
<400> 1
cagtgggtaa gttccttaaa tgctctgcaa agaaattggg acttttcatt aaatcagaaa 60
ttttactttt ttcccctcct gggagctaaa gatattttag agaagaatta accttttgct 120
tctccagttg aacatttgta gcaataagtc atgcaaatag agctctccac ctgcttcttt 180
ctgtgccttt tgcgattctg ctttagt gcc acc aga aga tac tac ctg ggt gca 234
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala
1 5
gtg gaa ctg tca tgg gac tat atg caa agt gat ctc ggt gag ctg cct 282
Val Glu Leu Ser Trp Asp Tyr Met Gln Ser Asp Leu Gly Glu Leu Pro
10 15 20 25
gtg gac gca aga ttt cct cct aga gtg cca aaa tct ttt cca ttc aac 330
Val Asp Ala Arg Phe Pro Pro Arg Val Pro Lys Ser Phe Pro Phe Asn
30 35 40
acc tca gtc gtg tac aaa aag act ctg ttt gta gaa ttc acg gtt cac 378
Thr Ser Val Val Tyr Lys Lys Thr Leu Phe Val Glu Phe Thr Val His
45 50 55
ctt ttc aac atc gct aag cca agg cca ccc tgg atg ggt ctg cta ggt 426
Leu Phe Asn Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly
60 65 70
cct acc atc cag gct gag gtt tat gat aca gtg gtc att aca ctt aag 474
Pro Thr Ile Gln Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys
75 80 85
aac atg gct tcc cat cct gtc agt ctt cat gct gtt ggt gta tcc tac 522
Asn Met Ala Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr
90 95 100 105
tgg aaa gct tct gag gga gct gaa tat gat gat cag acc agt caa agg 570
Trp Lys Ala Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg
110 115 120
gag aaa gaa gat gat aaa gtc ttc cct ggt gga agc cat aca tat gtc 618
Glu Lys Glu Asp Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr Val
125 130 135
tgg cag gtc ctg aaa gag aat ggt cca atg gcc tct gac cca ctg tgc 666
Trp Gln Val Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Leu Cys
140 145 150
ctt acc tac tca tat ctt tct cat gtg gac ctg gta aaa gac ttg aat 714
Leu Thr Tyr Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn
155 160 165
tca ggc ctc att gga gcc cta cta gta tgt aga gaa ggg agt ctg gcc 762
Ser Gly Leu Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala
170 175 180 185
aag gaa aag aca cag acc ttg cac aaa ttt ata cta ctt ttt gct gta 810
Lys Glu Lys Thr Gln Thr Leu His Lys Phe Ile Leu Leu Phe Ala Val
190 195 200
ttt gat gaa ggg aaa agt tgg cac tca gaa aca aag aac tcc ttg atg 858
Phe Asp Glu Gly Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu Met
205 210 215
cag gat agg gat gct gca tct gct cgg gcc tgg cct aaa atg cac aca 906
Gln Asp Arg Asp Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His Thr
220 225 230
gtc aat ggt tat gta aac agg tct ctg cca ggt ctg att gga tgc cac 954
Val Asn Gly Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His
235 240 245
agg aaa tca gtc tat tgg cat gtg att gga atg ggc acc act cct gaa 1002
Arg Lys Ser Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu
250 255 260 265
gtg cac tca ata ttc ctc gaa ggt cac aca ttt ctt gtg agg aac cat 1050
Val His Ser Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His
270 275 280
cgc cag gcg tcc ttg gaa atc tcg cca ata act ttc ctt act gct caa 1098
Arg Gln Ala Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln
285 290 295
aca ctc ttg atg gac ctt gga cag ttt cta ctg ttt tgt cat atc tct 1146
Thr Leu Leu Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser
300 305 310
tcc cac caa cat gat ggc atg gaa gct tat gtc aaa gta gac agc tgt 1194
Ser His Gln His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys
315 320 325
cca gag gaa ccc caa cta cga atg aaa aat aat gaa gaa gcg gaa gac 1242
Pro Glu Glu Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu Asp
330 335 340 345
tat gat gat gat ctt act gat tct gaa atg gat gtg gtc agg ttt gat 1290
Tyr Asp Asp Asp Leu Thr Asp Ser Glu Met Asp Val Val Arg Phe Asp
350 355 360
gat gac aac tct cct tcc ttt atc caa att cgc tca gtt gcc aag aag 1338
Asp Asp Asn Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys
365 370 375
cat cct aaa act tgg gta cat tac att gct gct gaa gag gag gac tgg 1386
His Pro Lys Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp
380 385 390
gac tat gct ccc tta gtc ctc gcc ccc gat gac aga agt tat aaa agt 1434
Asp Tyr Ala Pro Leu Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys Ser
395 400 405
caa tat ttg aac aat ggc cct cag cgg att ggt agg aag tac aaa aaa 1482
Gln Tyr Leu Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys
410 415 420 425
gtc cga ttt atg gca tac aca gat gaa acc ttt aag act cgt gaa gct 1530
Val Arg Phe Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala
430 435 440
att cag cat gaa tca gga atc ttg gga cct tta ctt tat ggg gaa gtt 1578
Ile Gln His Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val
445 450 455
gga gac aca ctg ttg att ata ttt aag aat caa gca agc aga cca tat 1626
Gly Asp Thr Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr
460 465 470
aac atc tac cct cac gga atc act gat gtc cgt cct ttg tat tca agg 1674
Asn Ile Tyr Pro His Gly Ile Thr Asp Val Arg Pro Leu Tyr Ser Arg
475 480 485
aga tta cca aaa ggt gta aaa cat ttg aag gat ttt cca att ctg cca 1722
Arg Leu Pro Lys Gly Val Lys His Leu Lys Asp Phe Pro Ile Leu Pro
490 495 500 505
gga gaa ata ttc aaa tat aaa tgg aca gtg act gta gaa gat ggg cca 1770
Gly Glu Ile Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro
510 515 520
act aaa tca gat cct cgg tgc ctg acc cgc tat tac tct agt ttc gtt 1818
Thr Lys Ser Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Val
525 530 535
aat atg gag aga gat cta gct tca gga ctc att ggc cct ctc ctc atc 1866
Asn Met Glu Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile
540 545 550
tgc tac aaa gaa tct gta gat caa aga gga aac cag ata atg tca gac 1914
Cys Tyr Lys Glu Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser Asp
555 560 565
aag agg aat gtc atc ctg ttt tct gta ttt gat gag aac cga agc tgg 1962
Lys Arg Asn Val Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp
570 575 580 585
tac ctc aca gag aat ata caa cgc ttt ctc ccc aat cca gct gga gtg 2010
Tyr Leu Thr Glu Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly Val
590 595 600
cag ctt gag gat cca gag ttc caa gcc tcc aac atc atg cac agc atc 2058
Gln Leu Glu Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile
605 610 615
aat ggc tat gtt ttt gat agt ttg cag ttg tca gtt tgt ttg cat gag 2106
Asn Gly Tyr Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu
620 625 630
gtg gca tac tgg tac att cta agc att gga gca cag act gac ttc ctt 2154
Val Ala Tyr Trp Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu
635 640 645
tct gtc ttc ttc tct gga tat acc ttc aaa cac aaa atg gtc tat gaa 2202
Ser Val Phe Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu
650 655 660 665
gac aca ctc acc cta ttc cca ttc tca gga gaa act gtc ttc atg tcg 2250
Asp Thr Leu Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser
670 675 680
atg gaa aac cca ggt cta tgg att ctg ggg tgc cac aac tca gac ttt 2298
Met Glu Asn Pro Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp Phe
685 690 695
cgg aac aga ggc atg acc gcc tta ctg aag gtt tct agt tgt gac aag 2346
Arg Asn Arg Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys
700 705 710
aac act ggt gat tat tac gag gac agt tat gaa gat att tca gca tac 2394
Asn Thr Gly Asp Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Ala Tyr
715 720 725
ttg ctg agt aaa aac aat gcc att gaa cca aga agc ttc tcc cag aat 2442
Leu Leu Ser Lys Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln Asn
730 735 740 745
tca aga cac cct agc act agg caa aag caa ttt aat gcc acc aca att 2490
Ser Arg His Pro Ser Thr Arg Gln Lys Gln Phe Asn Ala Thr Thr Ile
750 755 760
cca gaa aat gac ata gag aag act gac cct tgg ttt gca cac aga aca 2538
Pro Glu Asn Asp Ile Glu Lys Thr Asp Pro Trp Phe Ala His Arg Thr
765 770 775
cct atg cct aaa ata caa aat gtc tcc tct agt gat ttg ttg atg ctc 2586
Pro Met Pro Lys Ile Gln Asn Val Ser Ser Ser Asp Leu Leu Met Leu
780 785 790
ttg cga cag agt cct act cca cat ggg cta tcc tta tct gat ctc caa 2634
Leu Arg Gln Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln
795 800 805
gaa gcc aaa tat gag act ttt tct gat gat cca tca cct gga gca ata 2682
Glu Ala Lys Tyr Glu Thr Phe Ser Asp Asp Pro Ser Pro Gly Ala Ile
810 815 820 825
gac agt aat aac agc ctg tct gaa atg aca cac ttc agg cca cag ctc 2730
Asp Ser Asn Asn Ser Leu Ser Glu Met Thr His Phe Arg Pro Gln Leu
830 835 840
cat cac agt ggg gac atg gta ttt acc cct gag tca ggc ctc caa tta 2778
His His Ser Gly Asp Met Val Phe Thr Pro Glu Ser Gly Leu Gln Leu
845 850 855
aga tta aat gag aaa ctg ggg aca act gca gca aca gag ttg aag aaa 2826
Arg Leu Asn Glu Lys Leu Gly Thr Thr Ala Ala Thr Glu Leu Lys Lys
860 865 870
ctt gat ttc aaa gtt tct agt aca tca aat aat ctg att tca aca att 2874
Leu Asp Phe Lys Val Ser Ser Thr Ser Asn Asn Leu Ile Ser Thr Ile
875 880 885
cca tca gac aat ttg gca gca ggt act gat aat aca agt tcc tta gga 2922
Pro Ser Asp Asn Leu Ala Ala Gly Thr Asp Asn Thr Ser Ser Leu Gly
890 895 900 905
ccc cca agt atg cca gtt cat tat gat agt caa tta gat acc act cta 2970
Pro Pro Ser Met Pro Val His Tyr Asp Ser Gln Leu Asp Thr Thr Leu
910 915 920
ttt ggc aaa aag tca tct ccc ctt act gag tct ggt gga cct ctg agc 3018
Phe Gly Lys Lys Ser Ser Pro Leu Thr Glu Ser Gly Gly Pro Leu Ser
925 930 935
ttg agt gaa gaa aat aat gat tca aag ttg tta gaa tca ggt tta atg 3066
Leu Ser Glu Glu Asn Asn Asp Ser Lys Leu Leu Glu Ser Gly Leu Met
940 945 950
aat agc caa gaa agt tca tgg gga aaa aat gta tcg tca aca gag agt 3114
Asn Ser Gln Glu Ser Ser Trp Gly Lys Asn Val Ser Ser Thr Glu Ser
955 960 965
ggt agg tta ttt aaa ggg aaa aga gct cat gga cct gct ttg ttg act 3162
Gly Arg Leu Phe Lys Gly Lys Arg Ala His Gly Pro Ala Leu Leu Thr
970 975 980 985
aaa gat aat gcc tta ttc aaa gtt agc atc tct ttg tta aag aca aac 3210
Lys Asp Asn Ala Leu Phe Lys Val Ser Ile Ser Leu Leu Lys Thr Asn
990 995 1000
aaa act tcc aat aat tca gca act aat aga aag act cac att gat ggc 3258
Lys Thr Ser Asn Asn Ser Ala Thr Asn Arg Lys Thr His Ile Asp Gly
1005 1010 1015
cca tca tta tta att gag aat agt cca tca gtc tgg caa aat ata tta 3306
Pro Ser Leu Leu Ile Glu Asn Ser Pro Ser Val Trp Gln Asn Ile Leu
1020 1025 1030
gaa agt gac act gag ttt aaa aaa gtg aca cct ttg att cat gac aga 3354
Glu Ser Asp Thr Glu Phe Lys Lys Val Thr Pro Leu Ile His Asp Arg
1035 1040 1045
atg ctt atg gac aaa aat gct aca gct ttg agg cta aat cat atg tca 3402
Met Leu Met Asp Lys Asn Ala Thr Ala Leu Arg Leu Asn His Met Ser
1050 1055 1060 1065
aat aaa act act tca tca aaa aac atg gaa atg gtc caa cag aaa aaa 3450
Asn Lys Thr Thr Ser Ser Lys Asn Met Glu Met Val Gln Gln Lys Lys
1070 1075 1080
gag ggc ccc att cca cca gat gca caa aat cca gat atg tcg ttc ttt 3498
Glu Gly Pro Ile Pro Pro Asp Ala Gln Asn Pro Asp Met Ser Phe Phe
1085 1090 1095
aag atg cta ttc ttg cca gaa tca gca agg tgg ata caa agg act cat 3546
Lys Met Leu Phe Leu Pro Glu Ser Ala Arg Trp Ile Gln Arg Thr His
1100 1105 1110
gga aag aac tct ctg aac tct ggg caa ggc ccc agt cca aag caa tta 3594
Gly Lys Asn Ser Leu Asn Ser Gly Gln Gly Pro Ser Pro Lys Gln Leu
1115 1120 1125
gta tcc tta gga cca gaa aaa tct gtg gaa ggt cag aat ttc ttg tct 3642
Val Ser Leu Gly Pro Glu Lys Ser Val Glu Gly Gln Asn Phe Leu Ser
1130 1135 1140 1145
gag aaa aac aaa gtg gta gta gga aag ggt gaa ttt aca aag gac gta 3690
Glu Lys Asn Lys Val Val Val Gly Lys Gly Glu Phe Thr Lys Asp Val
1150 1155 1160
gga ctc aaa gag atg gtt ttt cca agc agc aga aac cta ttt ctt act 3738
Gly Leu Lys Glu Met Val Phe Pro Ser Ser Arg Asn Leu Phe Leu Thr
1165 1170 1175
aac ttg gat aat tta cat gaa aat aat aca cac aat caa gaa aaa aaa 3786
Asn Leu Asp Asn Leu His Glu Asn Asn Thr His Asn Gln Glu Lys Lys
1180 1185 1190
att cag gaa gaa ata gaa aag aag gaa aca tta atc caa gag aat gta 3834
Ile Gln Glu Glu Ile Glu Lys Lys Glu Thr Leu Ile Gln Glu Asn Val
1195 1200 1205
gtt ttg cct cag ata cat aca gtg act ggc act aag aat ttc atg aag 3882
Val Leu Pro Gln Ile His Thr Val Thr Gly Thr Lys Asn Phe Met Lys
1210 1215 1220 1225
aac ctt ttc tta ctg agc act agg caa aat gta gaa ggt tca tat gag 3930
Asn Leu Phe Leu Leu Ser Thr Arg Gln Asn Val Glu Gly Ser Tyr Glu
1230 1235 1240
ggg gca tat gct cca gta ctt caa gat ttt agg tca tta aat gat tca 3978
Gly Ala Tyr Ala Pro Val Leu Gln Asp Phe Arg Ser Leu Asn Asp Ser
1245 1250 1255
aca aat aga aca aag aaa cac aca gct cat ttc tca aaa aaa ggg gag 4026
Thr Asn Arg Thr Lys Lys His Thr Ala His Phe Ser Lys Lys Gly Glu
1260 1265 1270
gaa gaa aac ttg gaa ggc ttg gga aat caa acc aag caa att gta gag 4074
Glu Glu Asn Leu Glu Gly Leu Gly Asn Gln Thr Lys Gln Ile Val Glu
1275 1280 1285
aaa tat gca tgc acc aca agg ata tct cct aat aca agc cag cag aat 4122
Lys Tyr Ala Cys Thr Thr Arg Ile Ser Pro Asn Thr Ser Gln Gln Asn
1290 1295 1300 1305
ttt gtc acg caa cgt agt aag aga gct ttg aaa caa ttc aga ctc cca 4170
Phe Val Thr Gln Arg Ser Lys Arg Ala Leu Lys Gln Phe Arg Leu Pro
1310 1315 1320
cta gaa gaa aca gaa ctt gaa aaa agg ata att gtg gat gac acc tca 4218
Leu Glu Glu Thr Glu Leu Glu Lys Arg Ile Ile Val Asp Asp Thr Ser
1325 1330 1335
acc cag tgg tcc aaa aac atg aaa cat ttg acc ccg agc acc ctc aca 4266
Thr Gln Trp Ser Lys Asn Met Lys His Leu Thr Pro Ser Thr Leu Thr
1340 1345 1350
cag ata gac tac aat gag aag gag aaa ggg gcc att act cag tct ccc 4314
Gln Ile Asp Tyr Asn Glu Lys Glu Lys Gly Ala Ile Thr Gln Ser Pro
1355 1360 1365
tta tca gat tgc ctt acg agg agt cat agc atc cct caa gca aat aga 4362
Leu Ser Asp Cys Leu Thr Arg Ser His Ser Ile Pro Gln Ala Asn Arg
1370 1375 1380 1385
tct cca tta ccc att gca aag gta tca tca ttt cca tct att aga cct 4410
Ser Pro Leu Pro Ile Ala Lys Val Ser Ser Phe Pro Ser Ile Arg Pro
1390 1395 1400
ata tat ctg acc agg gtc cta ttc caa gac aac tct tct cat ctt cca 4458
Ile Tyr Leu Thr Arg Val Leu Phe Gln Asp Asn Ser Ser His Leu Pro
1405 1410 1415
gca gca tct tat aga aag aaa gat tct ggg gtc caa gaa agc agt cat 4506
Ala Ala Ser Tyr Arg Lys Lys Asp Ser Gly Val Gln Glu Ser Ser His
1420 1425 1430
ttc tta caa gga gcc aaa aaa aat aac ctt tct tta gcc att cta acc 4554
Phe Leu Gln Gly Ala Lys Lys Asn Asn Leu Ser Leu Ala Ile Leu Thr
1435 1440 1445
ttg gag atg act ggt gat caa aga gag gtt ggc tcc ctg ggg aca agt 4602
Leu Glu Met Thr Gly Asp Gln Arg Glu Val Gly Ser Leu Gly Thr Ser
1450 1455 1460 1465
gcc aca aat tca gtc aca tac aag aaa gtt gag aac act gtt ctc ccg 4650
Ala Thr Asn Ser Val Thr Tyr Lys Lys Val Glu Asn Thr Val Leu Pro
1470 1475 1480
aaa cca gac ttg ccc aaa aca tct ggc aaa gtt gaa ttg ctt cca aaa 4698
Lys Pro Asp Leu Pro Lys Thr Ser Gly Lys Val Glu Leu Leu Pro Lys
1485 1490 1495
gtt cac att tat cag aag gac cta ttc cct acg gaa act agc aat ggg 4746
Val His Ile Tyr Gln Lys Asp Leu Phe Pro Thr Glu Thr Ser Asn Gly
1500 1505 1510
tct cct ggc cat ctg gat ctc gtg gaa ggg agc ctt ctt cag gga aca 4794
Ser Pro Gly His Leu Asp Leu Val Glu Gly Ser Leu Leu Gln Gly Thr
1515 1520 1525
gag gga gcg att aag tgg aat gaa gca aac aga cct gga aaa gtt ccc 4842
Glu Gly Ala Ile Lys Trp Asn Glu Ala Asn Arg Pro Gly Lys Val Pro
1530 1535 1540 1545
ttt ctg aga gta gca aca gaa agc tct gca aag act ccc tcc aag cta 4890
Phe Leu Arg Val Ala Thr Glu Ser Ser Ala Lys Thr Pro Ser Lys Leu
1550 1555 1560
ttg gat cct ctt gct tgg gat aac cac tat ggt act cag ata cca aaa 4938
Leu Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro Lys
1565 1570 1575
gaa gag tgg aaa tcc caa gag aag tca cca gaa aaa aca gct ttt aag 4986
Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe Lys
1580 1585 1590
aaa aag gat acc att ttg tcc ctg aac gct tgt gaa agc aat cat gca 5034
Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His Ala
1595 1600 1605
ata gca gca ata aat gag gga caa aat aag ccc gaa ata gaa gtc acc 5082
Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu Val Thr
1610 1615 1620 1625
tgg gca aag caa ggt agg act gaa agg ctg tgc tct caa aac cca cca 5130
Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln Asn Pro Pro
1630 1635 1640
gtc ttg aaa cgc cat caa cgg gaa ata act cgt act act ctt cag tca 5178
Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln Ser
1645 1650 1655
gat caa gag gaa att gac tat gat gat acc ata tca gtt gaa atg aag 5226
Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys
1660 1665 1670
aag gaa gat ttt gac att tat gat gag gat gaa aat cag agc ccc cgc 5274
Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg
1675 1680 1685
agc ttt caa aag aaa aca cga cac tat ttt att gct gca gtg gag agg 5322
Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg
1690 1695 1700 1705
ctc tgg gat tat ggg atg agt agc tcc cca cat gtt cta aga aac agg 5370
Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg
1710 1715 1720
gct cag agt ggc agt gtc cct cag ttc aag aaa gtt gtt ttc cag gaa 5418
Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu
1725 1730 1735
ttt act gat ggc tcc ttt act cag ccc tta tac cgt gga gaa cta aat 5466
Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn
1740 1745 1750
gaa cat ttg gga ctc ctg ggg cca tat ata aga gca gaa gtt gaa gat 5514
Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp
1755 1760 1765
aat atc atg gta act ttc aga aat cag gcc tct cgt ccc tat tcc ttc 5562
Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe
1770 1775 1780 1785
tat tct agc ctt att tct tat gag gaa gat cag agg caa gga gca gaa 5610
Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu
1790 1795 1800
cct aga aaa aac ttt gtc aag cct aat gaa acc aaa act tac ttt tgg 5658
Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp
1805 1810 1815
aaa gtg caa cat cat atg gca ccc act aaa gat gag ttt gac tgc aaa 5706
Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys
1820 1825 1830
gcc tgg gct tat ttc tct gat gtt gac ctg gaa aaa gat gtg cac tca 5754
Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser
1835 1840 1845
ggc ctg att gga ccc ctt ctg gtc tgc cac act aac aca ctg aac cct 5802
Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro
1850 1855 1860 1865
gct cat ggg aga caa gtg aca gta cag gaa ttt gct ctg ttt ttc acc 5850
Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr
1870 1875 1880
atc ttt gat gag acc aaa agc tgg tac ttc act gaa aat atg gaa aga 5898
Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg
1885 1890 1895
aac tgc agg gct ccc tgc aat atc cag atg gaa gat ccc act ttt aaa 5946
Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys
1900 1905 1910
gag aat tat cgc ttc cat gca atc aat ggc tac ata atg gat aca cta 5994
Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu
1915 1920 1925
cct ggc tta gta atg gct cag gat caa agg att cga tgg tat ctg ctc 6042
Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu
1930 1935 1940 1945
agc atg ggc agc aat gaa aac atc cat tct att cat ttc agt gga cat 6090
Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly His
1950 1955 1960
gtg ttc act gta cga aaa aaa gag gag tat aaa atg gca ctg tac aat 6138
Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn
1965 1970 1975
ctc tat cca ggt gtt ttt gag aca gtg gaa atg tta cca tcc aaa gct 6186
Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys Ala
1980 1985 1990
gga att tgg cgg gtg gaa tgc ctt att ggc gag cat cta cat gct ggg 6234
Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala Gly
1995 2000 2005
atg agc aca ctt ttt ctg gtg tac agc aat aag tgt cag act ccc ctg 6282
Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu
2010 2015 2020 2025
gga atg gct tct gga cac att aga gat ttt cag att aca gct tca gga 6330
Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly
2030 2035 2040
caa tat gga cag tgg gcc cca aag ctg gcc aga ctt cat tat tcc gga 6378
Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly
2045 2050 2055
tca atc aat gcc tgg agc acc aag gag ccc ttt tct tgg atc aag gtg 6426
Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val
2060 2065 2070
gat ctg ttg gca cca atg att att cac ggc atc aag acc cag ggt gcc 6474
Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala
2075 2080 2085
cgt cag aag ttc tcc agc ctc tac atc tct cag ttt atc atc atg tat 6522
Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr
2090 2095 2100 2105
agt ctt gat ggg aag aag tgg cag act tat cga gga aat tcc act gga 6570
Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly
2110 2115 2120
acc tta atg gtc ttc ttt ggc aat gtg gat tca tct ggg ata aaa cac 6618
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His
2125 2130 2135
aat att ttt aac cct cca att att gct cga tac atc cgt ttg cac cca 6666
Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro
2140 2145 2150
act cat tat agc att cgc agc act ctt cgc atg gag ttg atg ggc tgt 6714
Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys
2155 2160 2165
gat tta aat agt tgc agc atg cca ttg gga atg gag agt aaa gca ata 6762
Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile
2170 2175 2180 2185
tca gat gca cag att act gct tca tcc tac ttt acc aat atg ttt gcc 6810
Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala
2190 2195 2200
acc tgg tct cct tca aaa gct cga ctt cac ctc caa ggg agg agt aat 6858
Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser Asn
2205 2210 2215
gcc tgg aga cct cag gtg aat aat cca aaa gag tgg ctg caa gtg gac 6906
Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val Asp
2220 2225 2230
ttc cag aag aca atg aaa gtc aca gga gta act act cag gga gta aaa 6954
Phe Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val Lys
2235 2240 2245
tct ctg ctt acc agc atg tat gtg aag gag ttc ctc atc tcc agc agt 7002
Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser
2250 2255 2260 2265
caa gat ggc cat cag tgg act ctc ttt ttt cag aat ggc aaa gta aag 7050
Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val Lys
2270 2275 2280
gtt ttt cag gga aat caa gac tcc ttc aca cct gtg gtg aac tct cta 7098
Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu
2285 2290 2295
gac cca ccg tta ctg act cgc tac ctt cga att cac ccc cag agt tgg 7146
Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp
2300 2305 2310
gtg cac cag att gcc ctg agg atg gag gtt ctg ggc tgc gag gca cag 7194
Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala Gln
2315 2320 2325
gac ctc tac tgagggtggc cactgcagca cctgccactg ccgtcacctc 7243
Asp Leu Tyr
2330
tccctcctca gctccagggc agtgtccctc cctggcttgc cttctacctt tgtgctaaat 7303
cctagcagac actgccttga agcctcctga attaactatc atcagtcctg catttctttg 7363
gtggggggcc aggagggtgc atccaattta acttaactct tacctatttt ctgcagctgc 7423
tcccagatta ctccttcctt ccaatataac taggcaaaaa gaagtgagga gaaacctgca 7483
tgaaagcatt cttccctgaa aagttaggcc tctcagagtc accacttcct ctgttgtaga 7543
aaaactatgt gatgaaactt tgaaaaagat atttatgatg ttaacatttc aggttaagcc 7603
tcatacgttt aaaataaaac tctcagttgt ttattatcct gatcaagcat ggaacaaagc 7663
atgtttcagg atcagatcaa tacaatcttg gagtcaaaag gcaaatcatt tggacaatct 7723
gcaaaatgga gagaatacaa taactactac agtaaagtct gtttctgctt ccttacacat 7783
agatataatt atgttattta gtcattatga ggggcacatt cttatctcca aaactagcat 7843
tcttaaactg agaattatag atggggttca agaatcccta agtcccctga aattatataa 7903
ggcattctgt ataaatgcaa atgtgcattt ttctgacgag tgtccataga tataaagcca 7963
ttggtcttaa ttctgaccaa taaaaaaata agtcaggagg atgcaattgt tgaaagcttt 8023
gaaataaaat aacatgtctt cttgaaattt gtgatggcca agaaagaaaa tgatgatgac 8083
attaggcttc taaaggacat acatttaata tttctgtgga aatatgagga aaatccatgg 8143
ttatctgaga taggagatac aaactttgta attctaataa tgcactcagt ttactctctc 8203
cctctactaa tttcctgctg aaaataacac aacaaaaatg taacagggga aattatatac 8263
cgtgactgaa aactagagtc ctacttacat agttgaaata tcaaggaggt cagaagaaaa 8323
ttggactggt gaaaacagaa aaaacactcc agtctgccat atcaccacac aataggatcc 8383
cccttcttgc cctccacccc cataagattg tgaagggttt actgctcctt ccatctgcct 8443
gcaccccttc actatgacta cacagaactc tcctgatagt aaagggggct ggaggcaagg 8503
ataagttata gagcagttgg aggaagcatc caaagactgc aacccagggc aaatggaaaa 8563
caggagatcc taatatgaaa gaaaaatgga tcccaatctg agaaaaggca aaagaatggc 8623
tacttttttc tatgctggag tattttctaa taatcctgct tgacccttat ctgacctctt 8683
tggaaactat aacatagctg tcacagtata gtcacaatcc acaaatgatg caggtgcaaa 8743
tggtttatag ccctgtgaag ttcttaaagt ttagaggcta acttacagaa atgaataagt 8803
tgttttgttt tatagcccgg tagaggagtt aaccccaaag gtgatatggt tttatttcct 8863
gttatgttta acttgataat cttattttgg cattcttttc ccattgacta tatacatctc 8923
tatttctcaa atgttcatgg aactagctct tttattttcc tgctggtttc ttcagtaatg 8983
agttaaataa aacattgaca cataca 9009
<210> 2
<211> 2332
<212> PRT
<213> Homo sapiens
<400> 2
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1 5 10 15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20 25 30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35 40 45
Thr Leu Phe Val Glu Phe Thr Val His Leu Phe Asn Ile Ala Lys Pro
50 55 60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65 70 75 80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85 90 95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100 105 110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115 120 125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130 135 140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145 150 155 160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165 170 175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180 185 190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195 200 205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210 215 220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225 230 235 240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245 250 255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260 265 270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275 280 285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290 295 300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305 310 315 320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325 330 335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340 345 350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355 360 365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370 375 380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385 390 395 400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405 410 415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420 425 430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435 440 445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450 455 460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465 470 475 480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485 490 495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500 505 510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515 520 525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530 535 540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545 550 555 560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565 570 575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580 585 590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe
595 600 605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610 615 620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625 630 635 640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645 650 655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660 665 670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675 680 685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690 695 700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705 710 715 720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725 730 735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg
740 745 750
Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys
755 760 765
Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn
770 775 780
Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro
785 790 795 800
His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe
805 810 815
Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser
820 825 830
Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val
835 840 845
Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly
850 855 860
Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser
865 870 875 880
Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala
885 890 895
Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met Pro Val His
900 905 910
Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys Ser Ser Pro
915 920 925
Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu Asn Asn Asp
930 935 940
Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu Ser Ser Trp
945 950 955 960
Gly Lys Asn Val Ser Ser Thr Glu Ser Gly Arg Leu Phe Lys Gly Lys
965 970 975
Arg Ala His Gly Pro Ala Leu Leu Thr Lys Asp Asn Ala Leu Phe Lys
980 985 990
Val Ser Ile Ser Leu Leu Lys Thr Asn Lys Thr Ser Asn Asn Ser Ala
995 1000 1005
Thr Asn Arg Lys Thr His Ile Asp Gly Pro Ser Leu Leu Ile Glu Asn
1010 1015 1020
Ser Pro Ser Val Trp Gln Asn Ile Leu Glu Ser Asp Thr Glu Phe Lys
1025 1030 1035 1040
Lys Val Thr Pro Leu Ile His Asp Arg Met Leu Met Asp Lys Asn Ala
1045 1050 1055
Thr Ala Leu Arg Leu Asn His Met Ser Asn Lys Thr Thr Ser Ser Lys
1060 1065 1070
Asn Met Glu Met Val Gln Gln Lys Lys Glu Gly Pro Ile Pro Pro Asp
1075 1080 1085
Ala Gln Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Glu
1090 1095 1100
Ser Ala Arg Trp Ile Gln Arg Thr His Gly Lys Asn Ser Leu Asn Ser
1105 1110 1115 1120
Gly Gln Gly Pro Ser Pro Lys Gln Leu Val Ser Leu Gly Pro Glu Lys
1125 1130 1135
Ser Val Glu Gly Gln Asn Phe Leu Ser Glu Lys Asn Lys Val Val Val
1140 1145 1150
Gly Lys Gly Glu Phe Thr Lys Asp Val Gly Leu Lys Glu Met Val Phe
1155 1160 1165
Pro Ser Ser Arg Asn Leu Phe Leu Thr Asn Leu Asp Asn Leu His Glu
1170 1175 1180
Asn Asn Thr His Asn Gln Glu Lys Lys Ile Gln Glu Glu Ile Glu Lys
1185 1190 1195 1200
Lys Glu Thr Leu Ile Gln Glu Asn Val Val Leu Pro Gln Ile His Thr
1205 1210 1215
Val Thr Gly Thr Lys Asn Phe Met Lys Asn Leu Phe Leu Leu Ser Thr
1220 1225 1230
Arg Gln Asn Val Glu Gly Ser Tyr Glu Gly Ala Tyr Ala Pro Val Leu
1235 1240 1245
Gln Asp Phe Arg Ser Leu Asn Asp Ser Thr Asn Arg Thr Lys Lys His
1250 1255 1260
Thr Ala His Phe Ser Lys Lys Gly Glu Glu Glu Asn Leu Glu Gly Leu
1265 1270 1275 1280
Gly Asn Gln Thr Lys Gln Ile Val Glu Lys Tyr Ala Cys Thr Thr Arg
1285 1290 1295
Ile Ser Pro Asn Thr Ser Gln Gln Asn Phe Val Thr Gln Arg Ser Lys
1300 1305 1310
Arg Ala Leu Lys Gln Phe Arg Leu Pro Leu Glu Glu Thr Glu Leu Glu
1315 1320 1325
Lys Arg Ile Ile Val Asp Asp Thr Ser Thr Gln Trp Ser Lys Asn Met
1330 1335 1340
Lys His Leu Thr Pro Ser Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys
1345 1350 1355 1360
Glu Lys Gly Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Leu Thr Arg
1365 1370 1375
Ser His Ser Ile Pro Gln Ala Asn Arg Ser Pro Leu Pro Ile Ala Lys
1380 1385 1390
Val Ser Ser Phe Pro Ser Ile Arg Pro Ile Tyr Leu Thr Arg Val Leu
1395 1400 1405
Phe Gln Asp Asn Ser Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys
1410 1415 1420
Asp Ser Gly Val Gln Glu Ser Ser His Phe Leu Gln Gly Ala Lys Lys
1425 1430 1435 1440
Asn Asn Leu Ser Leu Ala Ile Leu Thr Leu Glu Met Thr Gly Asp Gln
1445 1450 1455
Arg Glu Val Gly Ser Leu Gly Thr Ser Ala Thr Asn Ser Val Thr Tyr
1460 1465 1470
Lys Lys Val Glu Asn Thr Val Leu Pro Lys Pro Asp Leu Pro Lys Thr
1475 1480 1485
Ser Gly Lys Val Glu Leu Leu Pro Lys Val His Ile Tyr Gln Lys Asp
1490 1495 1500
Leu Phe Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu Asp Leu
1505 1510 1515 1520
Val Glu Gly Ser Leu Leu Gln Gly Thr Glu Gly Ala Ile Lys Trp Asn
1525 1530 1535
Glu Ala Asn Arg Pro Gly Lys Val Pro Phe Leu Arg Val Ala Thr Glu
1540 1545 1550
Ser Ser Ala Lys Thr Pro Ser Lys Leu Leu Asp Pro Leu Ala Trp Asp
1555 1560 1565
Asn His Tyr Gly Thr Gln Ile Pro Lys Glu Glu Trp Lys Ser Gln Glu
1570 1575 1580
Lys Ser Pro Glu Lys Thr Ala Phe Lys Lys Lys Asp Thr Ile Leu Ser
1585 1590 1595 1600
Leu Asn Ala Cys Glu Ser Asn His Ala Ile Ala Ala Ile Asn Glu Gly
1605 1610 1615
Gln Asn Lys Pro Glu Ile Glu Val Thr Trp Ala Lys Gln Gly Arg Thr
1620 1625 1630
Glu Arg Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg His Gln Arg
1635 1640 1645
Glu Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr
1650 1655 1660
Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr
1665 1670 1675 1680
Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg
1685 1690 1695
His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser
1700 1705 1710
Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro
1715 1720 1725
Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr
1730 1735 1740
Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly
1745 1750 1755 1760
Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Arg
1765 1770 1775
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr
1780 1785 1790
Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys
1795 1800 1805
Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala
1810 1815 1820
Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp
1825 1830 1835 1840
Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu
1845 1850 1855
Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr
1860 1865 1870
Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser
1875 1880 1885
Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn
1890 1895 1900
Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala
1905 1910 1915 1920
Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln
1925 1930 1935
Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn
1940 1945 1950
Ile His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys
1955 1960 1965
Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu
1970 1975 1980
Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys
1985 1990 1995 2000
Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val
2005 2010 2015
Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile
2020 2025 2030
Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro
2035 2040 2045
Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr
2050 2055 2060
Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile
2065 2070 2075 2080
Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu
2085 2090 2095
Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp
2100 2105 2110
Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly
2115 2120 2125
Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile
2130 2135 2140
Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser
2145 2150 2155 2160
Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met
2165 2170 2175
Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala
2180 2185 2190
Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala
2195 2200 2205
Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn
2210 2215 2220
Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val
2225 2230 2235 2240
Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
2245 2250 2255
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr
2260 2265 2270
Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp
2275 2280 2285
Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg
2290 2295 2300
Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg
2305 2310 2315 2320
Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
2325 2330
<210> 3
<211> 1130
<212> DNA
<213> Porcine
<400> 3
taagcaccct aagacgtggg tgcactacat ctctgcagag gaggaggact gggactacgc 60
ccccgcggtc cccagcccca gtgacagaag ttataaaagt ctctacttga acagtggtcc 120
tcagcgaatt ggtaggaaat acaaaaaagc tcgattcgtc gcttacacgg atgtaacatt 180
taagactcgt aaagctattc cgtatgaatc aggaatcctg ggacctttac tttatggaga 240
agttggagac acacttttga ttatatttaa gaataaagcg agccgaccat ataacatcta 300
ccctcatgga atcactgatg tcagcgcttt gcacccaggg agacttctaa aaggttggaa 360
acatttgaaa gacatgccaa ttctgccagg agagactttc aagtataaat ggacagtgac 420
tgtggaagat gggccaacca agtccgatcc tcggtgcctg acccgctact actcgagctc 480
cattaatcta gagaaagatc tggcttcggg actcattggc cctctcctca tctgctacaa 540
agaatctgta gaccaaagag gaaaccagat gatgtcagac aagagaaacg tcatcctgtt 600
ttctgtattc gatgagaatc aaagctggta cctcgcagag aatattcagc gcttcctccc 660
caatccggat ggattacagc cccaggatcc agagttccaa gcttctaaca tcatgcacag 720
catcaatggc tatgtttttg atagcttgca gctgtcggtt tgtttgcacg aggtggcata 780
ctggtacatt ctaagtgttg gagcacagac ggacttcctc tccgtcttct tctctggcta 840
caccttcaaa cacaaaatgg tctatgaaga cacactcacc ctgttcccct tctcaggaga 900
aacggtcttc atgtcaatgg aaaacccagg tctctgggtc ctagggtgcc acaactcaga 960
cttgcggaac agagggatga cagccttact gaaggtgtat agttgtgaca gggacattgg 1020
tgattattat gacaacactt atgaagatat tccaggcttc ttgctgagtg gaaagaatgt 1080
cattgaaccc agaagctttg cccagaattc aagaccccct agtgcgagca 1130
<210> 4
<211> 368
<212> PRT
<213> Porcine
<400> 4
Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His Tyr Ile Ser Ala
1 5 10 15
Glu Glu Glu Asp Trp Asp Tyr Ala Pro Ala Val Pro Ser Pro Ser Asp
20 25 30
Arg Ser Tyr Lys Ser Leu Tyr Leu Asn Ser Gly Pro Gln Arg Ile Gly
35 40 45
Arg Lys Tyr Lys Lys Ala Arg Phe Val Ala Tyr Thr Asp Val Thr Phe
50 55 60
Lys Thr Arg Lys Ala Ile Pro Tyr Glu Ser Gly Ile Leu Gly Pro Leu
65 70 75 80
Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile Phe Lys Asn Lys
85 90 95
Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile Thr Asp Val Ser
100 105 110
Ala Leu His Pro Gly Arg Leu Leu Lys Gly Trp Lys His Leu Lys Asp
115 120 125
Met Pro Ile Leu Pro Gly Glu Thr Phe Lys Tyr Lys Trp Thr Val Thr
130 135 140
Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys Leu Thr Arg Tyr
145 150 155 160
Tyr Ser Ser Ser Ile Asn Leu Glu Lys Asp Leu Ala Ser Gly Leu Ile
165 170 175
Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp Gln Arg Gly Asn
180 185 190
Gln Met Met Ser Asp Lys Arg Asn Val Ile Leu Phe Ser Val Phe Asp
195 200 205
Glu Asn Gln Ser Trp Tyr Leu Ala Glu Asn Ile Gln Arg Phe Leu Pro
210 215 220
Asn Pro Asp Gly Leu Gln Pro Gln Asp Pro Glu Phe Gln Ala Ser Asn
225 230 235 240
Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser Leu Gln Leu Ser
245 250 255
Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu Ser Val Gly Ala
260 265 270
Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr Thr Phe Lys His
275 280 285
Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro Phe Ser Gly Glu
290 295 300
Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp Val Leu Gly Cys
305 310 315 320
His Asn Ser Asp Leu Arg Asn Arg Gly Met Thr Ala Leu Leu Lys Val
325 330 335
Tyr Ser Cys Asp Arg Asp Ile Gly Asp Tyr Tyr Asp Asn Thr Tyr Glu
340 345 350
Asp Ile Pro Gly Phe Leu Leu Ser Gly Lys Asn Val Ile Glu Pro Arg
355 360 365
<210> 5
<211> 44
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 5
ctaatacgac tcactatagg gctcgagcgg ccgcccgggc aggt 44
<210> 6
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 6
ccatcctaat acgactcact atagggc 27
<210> 7
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 7
ccattgacat gaagaccgtt tctc 24
<210> 8
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 8
actcactata gggctcgagc ggc 23
<210> 9
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 9
gggtgcaaag cgctgacatc agtg 24
<210> 10
<211> 50
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 10
cctctcgagc caccatgtcg agccaccatg cagctagagc tctccacctg 50
<210> 11
<211> 31
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 11
cgcgcggccg cgcatctggc aaagctgagt t 31
<210> 12
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 12
gaaataagcc caggctttgc agtcraa 27
<210> 13
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<220>
<221> misc_feature
<222> (22)
<223> N at position 22 is A, T, G or C.
<400> 13
aggaaattcc actggaacct tn 22
<210> 14
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<220>
<221> misc_feature
<222> (25)
<223> N at position 25 is A, T, G or C.
<400> 14
ctgggggtga attcgaaggt agcgn 25
<210> 15
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 15
gagttcatcg ggaagacctg ttg 23
<210> 16
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:
Oligonucleotide primer
<400> 16
acagcccatc aactccatgc gaag 24
<210> 17
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 17
tcagggcaat caggactcc 19
<210> 18
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 18
ccgtggtgaa cgctctggac c 21
<210> 19
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 19
gtagaggtcc tgtgcctcgc agcc 24
<210> 20
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 20
gtagagstsc tgkgcctcrc akccyag 27
<210> 21
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 21
cttcgcatgg agttgatggg ctgt 24
<210> 22
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 22
aatcaggact cctccacccc g 21
<210> 23
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 23
ggatccaccc cacgagctgg 20
<210> 24
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 24
cgccctgagg ctcgaggttc tagg 24
<210> 25
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 25
aatcaggact cctccacccc cg 22
<210> 26
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 26
ccttgcagga attcgattca 20
<210> 27
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 27
ccgtggtgaa cgctctggac c 21
<210> 28
<211> 2319
<212> PRT
<213> Mus musculus
<400> 28
Met Gln Ile Ala Leu Phe Ala Cys Phe Phe Leu Ser Leu Phe Asn Phe
1 5 10 15
Cys Ser Ser Ala Ile Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asn Tyr Ile Gln Ser Asp Leu Leu Ser Val Leu His Thr Asp Ser
35 40 45
Arg Phe Leu Pro Arg Met Ser Thr Ser Phe Pro Phe Asn Thr Ser Ile
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Tyr Lys Asp Gln Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Trp Thr Glu Val His Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Asp Glu Tyr Glu Asp Gln Thr Ser Gln Met Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Met Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Lys Glu Gly Ser Leu Ser Lys Glu Arg
195 200 205
Thr Gln Met Leu Tyr Gln Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Asn Asp Ser Tyr Thr Gln Ser Met
225 230 235 240
Asp Ser Ala Ser Ala Arg Asp Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Ile His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Phe Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Ile Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Lys
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Ser Gln Trp Gln Lys Lys Asn Asn Asn Glu Glu Met Glu Asp Tyr Asp
355 360 365
Asp Asp Leu Tyr Ser Glu Met Asp Met Phe Thr Leu Asp Tyr Asp Ser
370 375 380
Ser Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys Tyr Pro Lys Thr
385 390 395 400
Trp Ile His Tyr Ile Ser Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro
405 410 415
Ser Val Pro Thr Ser Asp Asn Gly Ser Tyr Lys Ser Gln Tyr Leu Ser
420 425 430
Asn Gly Pro His Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Ile
435 440 445
Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Thr Ile Gln His Glu
450 455 460
Ser Gly Leu Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu
465 470 475 480
Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro
485 490 495
His Gly Ile Thr Asp Val Ser Pro Leu His Ala Arg Arg Leu Pro Arg
500 505 510
Gly Ile Lys His Val Lys Asp Leu Pro Ile His Pro Gly Glu Ile Phe
515 520 525
Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp
530 535 540
Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Pro Glu Arg
545 550 555 560
Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu
565 570 575
Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn Val
580 585 590
Ile Leu Phe Ser Ile Phe Asp Glu Asn Gln Ser Trp Tyr Ile Thr Glu
595 600 605
Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Lys Thr Gln Pro Gln Asp
610 615 620
Pro Gly Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
625 630 635 640
Phe Asp Ser Leu Glu Leu Thr Val Cys Leu His Glu Val Ala Tyr Trp
645 650 655
His Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Ile Phe Phe
660 665 670
Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr
675 680 685
Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro
690 695 700
Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Lys Arg Gly
705 710 715 720
Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Ser Thr Ser Asp
725 730 735
Tyr Tyr Glu Glu Ile Tyr Glu Asp Ile Pro Thr Gln Leu Val Asn Glu
740 745 750
Asn Asn Val Ile Asp Pro Arg Ser Phe Phe Gln Asn Thr Asn His Pro
755 760 765
Asn Thr Arg Lys Lys Lys Phe Lys Asp Ser Thr Ile Pro Lys Asn Asp
770 775 780
Met Glu Lys Ile Glu Pro Gln Phe Glu Glu Ile Ala Glu Met Leu Lys
785 790 795 800
Val Gln Ser Val Ser Val Ser Asp Met Leu Met Leu Leu Gly Gln Ser
805 810 815
His Pro Thr Pro His Gly Leu Phe Leu Ser Asp Gly Gln Glu Ala Ile
820 825 830
Tyr Glu Ala Ile His Asp Asp His Ser Pro Asn Ala Ile Asp Ser Asn
835 840 845
Glu Gly Pro Ser Lys Val Thr Gln Leu Arg Pro Glu Ser His His Ser
850 855 860
Glu Lys Ile Val Phe Thr Pro Gln Pro Gly Leu Gln Leu Arg Ser Asn
865 870 875 880
Lys Ser Leu Glu Thr Thr Ile Glu Val Lys Trp Lys Lys Leu Gly Leu
885 890 895
Gln Val Ser Ser Leu Pro Ser Asn Leu Met Thr Thr Thr Ile Leu Ser
900 905 910
Asp Asn Leu Lys Ala Thr Phe Glu Lys Thr Asp Ser Ser Gly Phe Pro
915 920 925
Asp Met Pro Val His Ser Ser Ser Lys Leu Ser Thr Thr Ala Phe Gly
930 935 940
Lys Lys Ala Tyr Ser Leu Val Gly Ser His Val Pro Leu Asn Ala Ser
945 950 955 960
Glu Glu Asn Ser Asp Ser Asn Ile Leu Asp Ser Thr Leu Met Tyr Ser
965 970 975
Gln Glu Ser Leu Pro Arg Asp Asn Ile Leu Ser Ile Glu Asn Asp Arg
980 985 990
Leu Leu Arg Glu Lys Arg Phe His Gly Ile Ala Leu Leu Thr Lys Asp
995 1000 1005
Asn Thr Leu Phe Lys Asp Asn Val Ser Leu Met Lys Thr Asn Lys Thr
1010 1015 1020
Tyr Asn His Ser Thr Thr Asn Glu Lys Leu His Thr Glu Ser Pro Thr
1025 1030 1035 1040
Ser Ile Glu Asn Ser Thr Thr Asp Leu Gln Asp Ala Ile Leu Lys Val
1045 1050 1055
Asn Ser Glu Ile Gln Glu Val Thr Ala Leu Ile His Asp Gly Thr Leu
1060 1065 1070
Leu Gly Lys Asn Ser Thr Tyr Leu Arg Leu Asn His Met Leu Asn Arg
1075 1080 1085
Thr Thr Ser Thr Lys Asn Lys Asp Ile Phe His Arg Lys Asp Glu Asp
1090 1095 1100
Pro Ile Pro Gln Asp Glu Glu Asn Thr Ile Met Pro Phe Ser Lys Met
1105 1110 1115 1120
Leu Phe Leu Ser Glu Ser Ser Asn Trp Phe Lys Lys Thr Asn Gly Asn
1125 1130 1135
Asn Ser Leu Asn Ser Glu Gln Glu His Ser Pro Lys Gln Leu Val Tyr
1140 1145 1150
Leu Met Phe Lys Lys Tyr Val Lys Asn Gln Ser Phe Leu Ser Glu Lys
1155 1160 1165
Asn Lys Val Thr Val Glu Gln Asp Gly Phe Thr Lys Asn Ile Gly Leu
1170 1175 1180
Lys Asp Met Ala Phe Pro His Asn Met Ser Ile Phe Leu Thr Thr Leu
1185 1190 1195 1200
Ser Asn Val His Glu Asn Gly Arg His Asn Gln Glu Lys Asn Ile Gln
1205 1210 1215
Glu Glu Ile Glu Lys Glu Ala Leu Ile Glu Glu Lys Val Val Leu Pro
1220 1225 1230
Gln Val His Glu Ala Thr Gly Ser Lys Asn Phe Leu Lys Asp Ile Leu
1235 1240 1245
Ile Leu Gly Thr Arg Gln Asn Ile Ser Leu Tyr Glu Val His Val Pro
1250 1255 1260
Val Leu Gln Asn Ile Thr Ser Ile Asn Asn Ser Thr Asn Thr Val Gln
1265 1270 1275 1280
Ile His Met Glu His Phe Phe Lys Arg Arg Lys Asp Lys Glu Thr Asn
1285 1290 1295
Ser Glu Gly Leu Val Asn Lys Thr Arg Glu Met Val Lys Asn Tyr Pro
1300 1305 1310
Ser Gln Lys Asn Ile Thr Thr Gln Arg Ser Lys Arg Ala Leu Gly Gln
1315 1320 1325
Phe Arg Leu Ser Thr Gln Trp Leu Lys Thr Ile Asn Cys Ser Thr Gln
1330 1335 1340
Cys Ile Ile Lys Gln Ile Asp His Ser Lys Glu Met Lys Lys Phe Ile
1345 1350 1355 1360
Thr Lys Ser Ser Leu Ser Asp Ser Ser Val Ile Lys Ser Thr Thr Gln
1365 1370 1375
Thr Asn Ser Ser Asp Ser His Ile Val Lys Thr Ser Ala Phe Pro Pro
1380 1385 1390
Ile Asp Leu Lys Arg Ser Pro Phe Gln Asn Lys Phe Ser His Val Gln
1395 1400 1405
Ala Ser Ser Tyr Ile Tyr Asp Phe Lys Thr Lys Ser Ser Arg Ile Gln
1410 1415 1420
Glu Ser Asn Asn Phe Leu Lys Glu Thr Lys Ile Asn Asn Pro Ser Leu
1425 1430 1435 1440
Ala Ile Leu Pro Trp Asn Met Phe Ile Asp Gln Gly Lys Phe Thr Ser
1445 1450 1455
Pro Gly Lys Ser Asn Thr Asn Ser Val Thr Tyr Lys Lys Arg Glu Asn
1460 1465 1470
Ile Ile Phe Leu Lys Pro Thr Leu Pro Glu Glu Ser Gly Lys Ile Glu
1475 1480 1485
Leu Leu Pro Gln Val Ser Ile Gln Glu Glu Glu Ile Leu Pro Thr Glu
1490 1495 1500
Thr Ser His Gly Ser Pro Gly His Leu Asn Leu Met Lys Glu Val Phe
1505 1510 1515 1520
Leu Gln Lys Ile Gln Gly Pro Thr Lys Trp Asn Lys Ala Lys Arg His
1525 1530 1535
Gly Glu Ser Ile Lys Gly Lys Thr Glu Ser Ser Lys Asn Thr Arg Ser
1540 1545 1550
Lys Leu Leu Asn His His Ala Trp Asp Tyr His Tyr Ala Ala Gln Ile
1555 1560 1565
Pro Lys Asp Met Trp Lys Ser Lys Glu Lys Ser Pro Glu Ile Ile Ser
1570 1575 1580
Ile Lys Gln Glu Asp Thr Ile Leu Ser Leu Arg Pro His Gly Asn Ser
1585 1590 1595 1600
His Ser Ile Gly Ala Asn Glu Lys Gln Asn Trp Pro Gln Arg Glu Thr
1605 1610 1615
Thr Trp Val Lys Gln Gly Gln Thr Gln Arg Thr Cys Ser Gln Ile Pro
1620 1625 1630
Pro Val Leu Lys Arg His Gln Arg Glu Leu Ser Ala Phe Gln Ser Glu
1635 1640 1645
Gln Glu Ala Thr Asp Tyr Asp Asp Ala Ile Thr Ile Glu Thr Ile Glu
1650 1655 1660
Asp Phe Asp Ile Tyr Ser Glu Asp Ile Lys Gln Gly Pro Arg Ser Phe
1665 1670 1675 1680
Gln Gln Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp
1685 1690 1695
Asp Tyr Gly Met Ser Thr Ser His Val Leu Arg Asn Arg Tyr Gln Ser
1700 1705 1710
Asp Asn Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp
1715 1720 1725
Gly Ser Phe Ser Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu
1730 1735 1740
Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met
1745 1750 1755 1760
Val Thr Phe Lys Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser
1765 1770 1775
Leu Ile Ser Tyr Lys Glu Asp Gln Arg Gly Glu Glu Pro Arg Arg Asn
1780 1785 1790
Phe Val Lys Pro Asn Glu Thr Lys Ile Tyr Phe Trp Lys Val Gln His
1795 1800 1805
His Met Ala Pro Thr Glu Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr
1810 1815 1820
Phe Ser Asp Val Asp Leu Glu Arg Asp Met His Ser Gly Leu Ile Gly
1825 1830 1835 1840
Pro Leu Leu Ile Cys His Ala Asn Thr Leu Asn Pro Ala His Gly Arg
1845 1850 1855
Gln Val Ser Val Gln Glu Phe Ala Leu Leu Phe Thr Ile Phe Asp Glu
1860 1865 1870
Thr Lys Ser Trp Tyr Phe Thr Glu Asn Val Lys Arg Asn Cys Lys Thr
1875 1880 1885
Pro Cys Asn Phe Gln Met Glu Asp Pro Thr Leu Lys Glu Asn Tyr Arg
1890 1895 1900
Phe His Ala Ile Asn Gly Tyr Val Met Asp Thr Leu Pro Gly Leu Val
1905 1910 1915 1920
Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Asn
1925 1930 1935
Asn Glu Asn Ile Gln Ser Ile His Phe Ser Gly His Val Phe Thr Val
1940 1945 1950
Arg Lys Lys Glu Glu Tyr Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly
1955 1960 1965
Val Phe Glu Thr Leu Glu Met Ile Pro Ser Arg Ala Gly Ile Trp Arg
1970 1975 1980
Val Glu Cys Leu Ile Gly Glu His Leu Gln Ala Gly Met Ser Thr Leu
1985 1990 1995 2000
Phe Leu Val Tyr Ser Lys Gln Cys Gln Ile Pro Leu Gly Met Ala Ser
2005 2010 2015
Gly Ser Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly His Tyr Gly Gln
2020 2025 2030
Trp Ala Pro Asn Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
2035 2040 2045
Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala
2050 2055 2060
Pro Met Ile Val His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe
2065 2070 2075 2080
Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly
2085 2090 2095
Lys Lys Trp Leu Ser Tyr Gln Gly Asn Ser Thr Gly Thr Leu Met Val
2100 2105 2110
Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ser Phe Asn
2115 2120 2125
Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Ser Ser
2130 2135 2140
Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser
2145 2150 2155 2160
Cys Ser Ile Pro Leu Gly Met Glu Ser Lys Val Ile Ser Asp Thr Gln
2165 2170 2175
Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro
2180 2185 2190
Ser Gln Ala Arg Leu His Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro
2195 2200 2205
Gln Val Asn Asp Pro Lys Gln Trp Leu Gln Val Asp Leu Gln Lys Thr
2210 2215 2220
Met Lys Val Thr Gly Ile Ile Thr Gln Gly Val Lys Ser Leu Phe Thr
2225 2230 2235 2240
Ser Met Phe Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His
2245 2250 2255
His Trp Thr Gln Ile Leu Tyr Asn Gly Lys Val Lys Val Phe Gln Gly
2260 2265 2270
Asn Gln Asp Ser Ser Thr Pro Met Met Asn Ser Leu Asp Pro Pro Leu
2275 2280 2285
Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ile Trp Glu His Gln Ile
2290 2295 2300
Ala Leu Arg Leu Glu Ile Leu Gly Cys Glu Ala Gln Gln Gln Tyr
2305 2310 2315
<210> 29
<211> 6402
<212> DNA
<213> Porcine
<220>
<221> CDS
<222> (1)..(6399)
<400> 29
atg cag cta gag ctc tcc acc tgt gtc ttt ctg tgt ctc ttg cca ctc 48
Met Gln Leu Glu Leu Ser Thr Cys Val Phe Leu Cys Leu Leu Pro Leu
1 5 10 15
ggc ttt agt gcc atc agg aga tac tac ctg ggc gca gtg gaa ctg tcc 96
Gly Phe Ser Ala Ile Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
tgg gac tac cgg caa agt gaa ctc ctc cgt gag ctg cac gtg gac acc 144
Trp Asp Tyr Arg Gln Ser Glu Leu Leu Arg Glu Leu His Val Asp Thr
35 40 45
aga ttt cct gct aca gcg cca gga gct ctt ccg ttg ggc ccg tca gtc 192
Arg Phe Pro Ala Thr Ala Pro Gly Ala Leu Pro Leu Gly Pro Ser Val
50 55 60
ctg tac aaa aag act gtg ttc gta gag ttc acg gat caa ctt ttc agc 240
Leu Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp Gln Leu Phe Ser
65 70 75 80
gtt gcc agg ccc agg cca cca tgg atg ggt ctg ctg ggt cct acc atc 288
Val Ala Arg Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
cag gct gag gtt tac gac acg gtg gtc gtt acc ctg aag aac atg gct 336
Gln Ala Glu Val Tyr Asp Thr Val Val Val Thr Leu Lys Asn Met Ala
100 105 110
tct cat ccc gtt agt ctt cac gct gtc ggc gtc tcc ttc tgg aaa tct 384
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Phe Trp Lys Ser
115 120 125
tcc gaa ggc gct gaa tat gag gat cac acc agc caa agg gag aag gaa 432
Ser Glu Gly Ala Glu Tyr Glu Asp His Thr Ser Gln Arg Glu Lys Glu
130 135 140
gac gat aaa gtc ctt ccc ggt aaa agc caa acc tac gtc tgg cag gtc 480
Asp Asp Lys Val Leu Pro Gly Lys Ser Gln Thr Tyr Val Trp Gln Val
145 150 155 160
ctg aaa gaa aat ggt cca aca gcc tct gac cca cca tgt ctc acc tac 528
Leu Lys Glu Asn Gly Pro Thr Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
tca tac ctg tct cac gtg gac ctg gtg aaa gac ctg aat tcg ggc ctc 576
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
att gga gcc ctg ctg gtt tgt aga gaa ggg agt ctg acc aga gaa agg 624
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Thr Arg Glu Arg
195 200 205
acc cag aac ctg cac gaa ttt gta cta ctt ttt gct gtc ttt gat gaa 672
Thr Gln Asn Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
ggg aaa agt tgg cac tca gca aga aat gac tcc tgg aca cgg gcc atg 720
Gly Lys Ser Trp His Ser Ala Arg Asn Asp Ser Trp Thr Arg Ala Met
225 230 235 240
gat ccc gca cct gcc agg gcc cag cct gca atg cac aca gtc aat ggc 768
Asp Pro Ala Pro Ala Arg Ala Gln Pro Ala Met His Thr Val Asn Gly
245 250 255
tat gtc aac agg tct ctg cca ggt ctg atc gga tgt cat aag aaa tca 816
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Lys Lys Ser
260 265 270
gtc tac tgg cac gtg att gga atg ggc acc agc ccg gaa gtg cac tcc 864
Val Tyr Trp His Val Ile Gly Met Gly Thr Ser Pro Glu Val His Ser
275 280 285
att ttt ctt gaa ggc cac acg ttt ctc gtg agg cac cat cgc cag gct 912
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg His His Arg Gln Ala
290 295 300
tcc ttg gag atc tcg cca cta act ttc ctc act gct cag aca ttc ctg 960
Ser Leu Glu Ile Ser Pro Leu Thr Phe Leu Thr Ala Gln Thr Phe Leu
305 310 315 320
atg gac ctt ggc cag ttc cta ctg ttt tgt cat atc tct tcc cac cac 1008
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His His
325 330 335
cat ggt ggc atg gag gct cac gtc aga gta gaa agc tgc gcc gag gag 1056
His Gly Gly Met Glu Ala His Val Arg Val Glu Ser Cys Ala Glu Glu
340 345 350
ccc cag ctg cgg agg aaa gct gat gaa gag gaa gat tat gat gac aat 1104
Pro Gln Leu Arg Arg Lys Ala Asp Glu Glu Glu Asp Tyr Asp Asp Asn
355 360 365
ttg tac gac tcg gac atg gac gtg gtc cgg ctc gat ggt gac gac gtg 1152
Leu Tyr Asp Ser Asp Met Asp Val Val Arg Leu Asp Gly Asp Asp Val
370 375 380
tct ccc ttt atc caa atc cgc tcg gtt gcc aag aag cat ccc aaa acc 1200
Ser Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr
385 390 395 400
tgg gtg cac tac atc tct gca gag gag gag gac tgg gac tac gcc ccc 1248
Trp Val His Tyr Ile Ser Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro
405 410 415
gcg gtc ccc agc ccc agt gac aga agt tat aaa agt ctc tac ttg aac 1296
Ala Val Pro Ser Pro Ser Asp Arg Ser Tyr Lys Ser Leu Tyr Leu Asn
420 425 430
agt ggt cct cag cga att ggt agg aaa tac aaa aaa gct cga ttc gtc 1344
Ser Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Ala Arg Phe Val
435 440 445
gct tac acg gat gta aca ttt aag act cgt aaa gct att ccg tat gaa 1392
Ala Tyr Thr Asp Val Thr Phe Lys Thr Arg Lys Ala Ile Pro Tyr Glu
450 455 460
tca gga atc ctg gga cct tta ctt tat gga gaa gtt gga gac aca ctt 1440
Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu
465 470 475 480
ttg att ata ttt aag aat aaa gcg agc cga cca tat aac atc tac cct 1488
Leu Ile Ile Phe Lys Asn Lys Ala Ser Arg Pro Tyr Asn Ile Tyr Pro
485 490 495
cat gga atc act gat gtc agc gct ttg cac cca ggg aga ctt cta aaa 1536
His Gly Ile Thr Asp Val Ser Ala Leu His Pro Gly Arg Leu Leu Lys
500 505 510
ggt tgg aaa cat ttg aaa gac atg cca att ctg cca gga gag act ttc 1584
Gly Trp Lys His Leu Lys Asp Met Pro Ile Leu Pro Gly Glu Thr Phe
515 520 525
aag tat aaa tgg aca gtg act gtg gaa gat ggg cca acc aag tcc gat 1632
Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp
530 535 540
cct cgg tgc ctg acc cgc tac tac tcg agc tcc att aat cta gag aaa 1680
Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Ser Ile Asn Leu Glu Lys
545 550 555 560
gat ctg gct tcg gga ctc att ggc cct ctc ctc atc tgc tac aaa gaa 1728
Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu
565 570 575
tct gta gac caa aga gga aac cag atg atg tca gac aag aga aac gtc 1776
Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn Val
580 585 590
atc ctg ttt tct gta ttc gat gag aat caa agc tgg tac ctc gca gag 1824
Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Ala Glu
595 600 605
aat att cag cgc ttc ctc ccc aat ccg gat gga tta cag ccc cag gat 1872
Asn Ile Gln Arg Phe Leu Pro Asn Pro Asp Gly Leu Gln Pro Gln Asp
610 615 620
cca gag ttc caa gct tct aac atc atg cac agc atc aat ggc tat gtt 1920
Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
625 630 635 640
ttt gat agc ttg cag ctg tcg gtt tgt ttg cac gag gtg gca tac tgg 1968
Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp
645 650 655
tac att cta agt gtt gga gca cag acg gac ttc ctc tcc gtc ttc ttc 2016
Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe
660 665 670
tct ggc tac acc ttc aaa cac aaa atg gtc tat gaa gac aca ctc acc 2064
Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr
675 680 685
ctg ttc ccc ttc tca gga gaa acg gtc ttc atg tca atg gaa aac cca 2112
Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro
690 695 700
ggt ctc tgg gtc cta ggg tgc cac aac tca gac ttg cgg aac aga ggg 2160
Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Leu Arg Asn Arg Gly
705 710 715 720
atg aca gcc tta ctg aag gtg tat agt tgt gac agg gac att ggt gat 2208
Met Thr Ala Leu Leu Lys Val Tyr Ser Cys Asp Arg Asp Ile Gly Asp
725 730 735
tat tat gac aac act tat gaa gat att cca ggc ttc ttg ctg agt gga 2256
Tyr Tyr Asp Asn Thr Tyr Glu Asp Ile Pro Gly Phe Leu Leu Ser Gly
740 745 750
aag aat gtc att gaa ccc aga agc ttt gcc cag aat tca aga ccc cct 2304
Lys Asn Val Ile Glu Pro Arg Ser Phe Ala Gln Asn Ser Arg Pro Pro
755 760 765
agt gcg agc caa aag caa ttc caa acc atc aca agt cca gaa gat gac 2352
Ser Ala Ser Gln Lys Gln Phe Gln Thr Ile Thr Ser Pro Glu Asp Asp
770 775 780
gtg gag ctt gac ccg cag tct gga gag aga acc caa gca ctg gaa gaa 2400
Val Glu Leu Asp Pro Gln Ser Gly Glu Arg Thr Gln Ala Leu Glu Glu
785 790 795 800
cta agt gtc ccc tct ggt gat ggg tcg atg ctc ttg gga cag aat cct 2448
Leu Ser Val Pro Ser Gly Asp Gly Ser Met Leu Leu Gly Gln Asn Pro
805 810 815
gct cca cat ggc tca tcc tca tct gat ctt caa gaa gcc agg aat gag 2496
Ala Pro His Gly Ser Ser Ser Ser Asp Leu Gln Glu Ala Arg Asn Glu
820 825 830
gct gat gat tat tta cct gga gca aga gaa aga ggc acg gcc cca tcc 2544
Ala Asp Asp Tyr Leu Pro Gly Ala Arg Glu Arg Gly Thr Ala Pro Ser
835 840 845
gca gcg gca cgt ctc aga cca gag ctg cat cac agt gcc gaa aga gta 2592
Ala Ala Ala Arg Leu Arg Pro Glu Leu His His Ser Ala Glu Arg Val
850 855 860
ctt act cct gag cca gag aaa gag ttg aag aaa ctt gat tca aaa atg 2640
Leu Thr Pro Glu Pro Glu Lys Glu Leu Lys Lys Leu Asp Ser Lys Met
865 870 875 880
tct agt tca tca gac ctt cta aag act tcg cca aca att cca tca gac 2688
Ser Ser Ser Ser Asp Leu Leu Lys Thr Ser Pro Thr Ile Pro Ser Asp
885 890 895
acg ttg tca gcg gag act gaa agg aca cat tcc tta ggc ccc cca cac 2736
Thr Leu Ser Ala Glu Thr Glu Arg Thr His Ser Leu Gly Pro Pro His
900 905 910
ccg cag gtt aat ttc agg agt caa tta ggt gcc att gta ctt ggc aaa 2784
Pro Gln Val Asn Phe Arg Ser Gln Leu Gly Ala Ile Val Leu Gly Lys
915 920 925
aat tca tct cac ttt att ggg gct ggt gtc cct ttg ggc tcg act gag 2832
Asn Ser Ser His Phe Ile Gly Ala Gly Val Pro Leu Gly Ser Thr Glu
930 935 940
gag gat cat gaa agc tcc ctg gga gaa aat gta tca cca gtg gag agt 2880
Glu Asp His Glu Ser Ser Leu Gly Glu Asn Val Ser Pro Val Glu Ser
945 950 955 960
gac ggg ata ttt gaa aag gaa aga gct cat gga cct gct tca ctg acc 2928
Asp Gly Ile Phe Glu Lys Glu Arg Ala His Gly Pro Ala Ser Leu Thr
965 970 975
aaa gac gat gtt tta ttt aaa gtt aat atc tct ttg gta aag aca aac 2976
Lys Asp Asp Val Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
980 985 990
aag gca cga gtt tac tta aaa act aat aga aag att cac att gat gac 3024
Lys Ala Arg Val Tyr Leu Lys Thr Asn Arg Lys Ile His Ile Asp Asp
995 1000 1005
gca gct tta tta act gag aat agg gca tct gca acg ttt atg gac aaa 3072
Ala Ala Leu Leu Thr Glu Asn Arg Ala Ser Ala Thr Phe Met Asp Lys
1010 1015 1020
aat act aca gct tcg gga tta aat cat gtg tca aat tgg ata aaa ggg 3120
Asn Thr Thr Ala Ser Gly Leu Asn His Val Ser Asn Trp Ile Lys Gly
1025 1030 1035 1040
ccc ctt ggc aag aac ccc cta agc tcg gag cga ggc ccc agt cca gag 3168
Pro Leu Gly Lys Asn Pro Leu Ser Ser Glu Arg Gly Pro Ser Pro Glu
1045 1050 1055
ctt ctg aca tct tca gga tca gga aaa tct gtg aaa ggt cag agt tct 3216
Leu Leu Thr Ser Ser Gly Ser Gly Lys Ser Val Lys Gly Gln Ser Ser
1060 1065 1070
ggg cag ggg aga ata cgg gtg gca gtg gaa gag gaa gaa ctg agc aaa 3264
Gly Gln Gly Arg Ile Arg Val Ala Val Glu Glu Glu Glu Leu Ser Lys
1075 1080 1085
ggc aaa gag atg atg ctt ccc aac agc gag ctc acc ttt ctc act aac 3312
Gly Lys Glu Met Met Leu Pro Asn Ser Glu Leu Thr Phe Leu Thr Asn
1090 1095 1100
tcg gct gat gtc caa gga aac gat aca cac agt caa gga aaa aag tct 3360
Ser Ala Asp Val Gln Gly Asn Asp Thr His Ser Gln Gly Lys Lys Ser
1105 1110 1115 1120
cgg gaa gag atg gaa agg aga gaa aaa tta gtc caa gaa aaa gtc gac 3408
Arg Glu Glu Met Glu Arg Arg Glu Lys Leu Val Gln Glu Lys Val Asp
1125 1130 1135
ttg cct cag gtg tat aca gcg act gga act aag aat ttc ctg aga aac 3456
Leu Pro Gln Val Tyr Thr Ala Thr Gly Thr Lys Asn Phe Leu Arg Asn
1140 1145 1150
att ttt cac caa agc act gag ccc agt gta gaa ggg ttt gat ggg ggg 3504
Ile Phe His Gln Ser Thr Glu Pro Ser Val Glu Gly Phe Asp Gly Gly
1155 1160 1165
tca cat gcg ccg gtg cct caa gac agc agg tca tta aat gat tcg gca 3552
Ser His Ala Pro Val Pro Gln Asp Ser Arg Ser Leu Asn Asp Ser Ala
1170 1175 1180
gag aga gca gag act cac ata gcc cat ttc tca gca att agg gaa gag 3600
Glu Arg Ala Glu Thr His Ile Ala His Phe Ser Ala Ile Arg Glu Glu
1185 1190 1195 1200
gca ccc ttg gaa gcc ccg gga aat cga aca ggt cca ggt ccg agg agt 3648
Ala Pro Leu Glu Ala Pro Gly Asn Arg Thr Gly Pro Gly Pro Arg Ser
1205 1210 1215
gcg gtt ccc cgc cgc gtt aag cag agc ttg aaa cag atc aga ctc ccg 3696
Ala Val Pro Arg Arg Val Lys Gln Ser Leu Lys Gln Ile Arg Leu Pro
1220 1225 1230
cta gaa gaa ata aag cct gaa agg ggg gtg gtt ctg aat gcc acc tca 3744
Leu Glu Glu Ile Lys Pro Glu Arg Gly Val Val Leu Asn Ala Thr Ser
1235 1240 1245
acc cgg tgg tct gaa agc agt cct atc tta caa gga gcc aaa aga aat 3792
Thr Arg Trp Ser Glu Ser Ser Pro Ile Leu Gln Gly Ala Lys Arg Asn
1250 1255 1260
aac ctt tct tta cct ttc ctg acc ttg gaa atg gcc gga ggt caa gga 3840
Asn Leu Ser Leu Pro Phe Leu Thr Leu Glu Met Ala Gly Gly Gln Gly
1265 1270 1275 1280
aag atc agc gcc ctg ggg aaa agt gcc gca ggc ccg ctg gcg tcc ggg 3888
Lys Ile Ser Ala Leu Gly Lys Ser Ala Ala Gly Pro Leu Ala Ser Gly
1285 1290 1295
aag ctg gag aag gct gtt ctc tct tca gca ggc ttg tct gaa gca tct 3936
Lys Leu Glu Lys Ala Val Leu Ser Ser Ala Gly Leu Ser Glu Ala Ser
1300 1305 1310
ggc aaa gct gag ttt ctt cct aaa gtt cga gtt cat cgg gaa gac ctg 3984
Gly Lys Ala Glu Phe Leu Pro Lys Val Arg Val His Arg Glu Asp Leu
1315 1320 1325
ttg cct caa aaa acc agc aat gtt tct tgc gca cac ggg gat ctc ggc 4032
Leu Pro Gln Lys Thr Ser Asn Val Ser Cys Ala His Gly Asp Leu Gly
1330 1335 1340
cag gag atc ttc ctg cag aaa aca cgg gga cct gtt aac ctg aac aaa 4080
Gln Glu Ile Phe Leu Gln Lys Thr Arg Gly Pro Val Asn Leu Asn Lys
1345 1350 1355 1360
gta aat aga cct gga agg act ccc tcc aag ctt ctg ggt ccc ccg atg 4128
Val Asn Arg Pro Gly Arg Thr Pro Ser Lys Leu Leu Gly Pro Pro Met
1365 1370 1375
ccc aaa gag tgg gaa tcc cta gag aag tca cca aaa agc aca gct ctc 4176
Pro Lys Glu Trp Glu Ser Leu Glu Lys Ser Pro Lys Ser Thr Ala Leu
1380 1385 1390
agg acg aaa gac atc atc agt tta ccc ctg gac cgt cac gaa agc aat 4224
Arg Thr Lys Asp Ile Ile Ser Leu Pro Leu Asp Arg His Glu Ser Asn
1395 1400 1405
cat tca ata gca gca aaa aat gaa gga caa gcc gag acc caa aga gaa 4272
His Ser Ile Ala Ala Lys Asn Glu Gly Gln Ala Glu Thr Gln Arg Glu
1410 1415 1420
gcc gcc tgg acg aag cag gga ggg cct gga agg ctg tgc gct cca aag 4320
Ala Ala Trp Thr Lys Gln Gly Gly Pro Gly Arg Leu Cys Ala Pro Lys
1425 1430 1435 1440
cct ccg gtc ctg cga cgg cat cag agg gac ata agc ctt cct act ttt 4368
Pro Pro Val Leu Arg Arg His Gln Arg Asp Ile Ser Leu Pro Thr Phe
1445 1450 1455
cag ccg gag gaa gac aaa atg gac tat gat gat atc ttc tca act gaa 4416
Gln Pro Glu Glu Asp Lys Met Asp Tyr Asp Asp Ile Phe Ser Thr Glu
1460 1465 1470
acg aag gga gaa gat ttt gac att tac ggt gag gat gaa aat cag gac 4464
Thr Lys Gly Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Asp
1475 1480 1485
cct cgc agc ttt cag aag aga acc cga cac tat ttc att gct gcg gtg 4512
Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala Ala Val
1490 1495 1500
gag cag ctc tgg gat tac ggg atg agc gaa tcc ccc cgg gcg cta aga 4560
Glu Gln Leu Trp Asp Tyr Gly Met Ser Glu Ser Pro Arg Ala Leu Arg
1505 1510 1515 1520
aac agg gct cag aac gga gag gtg cct cgg ttc aag aag gtg gtc ttc 4608
Asn Arg Ala Gln Asn Gly Glu Val Pro Arg Phe Lys Lys Val Val Phe
1525 1530 1535
cgg gaa ttt gct gac ggc tcc ttc acg cag ccg tcg tac cgc ggg gaa 4656
Arg Glu Phe Ala Asp Gly Ser Phe Thr Gln Pro Ser Tyr Arg Gly Glu
1540 1545 1550
ctc aac aaa cac ttg ggg ctc ttg gga ccc tac atc aga gcg gaa gtt 4704
Leu Asn Lys His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val
1555 1560 1565
gaa gac aac atc atg gta act ttc aaa aac cag gcg tct cgt ccc tat 4752
Glu Asp Asn Ile Met Val Thr Phe Lys Asn Gln Ala Ser Arg Pro Tyr
1570 1575 1580
tcc ttc tac tcg agc ctt att tct tat ccg gat gat cag gag caa ggg 4800
Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Pro Asp Asp Gln Glu Gln Gly
1585 1590 1595 1600
gca gaa cct cga cac aac ttc gtc cag cca aat gaa acc aga act tac 4848
Ala Glu Pro Arg His Asn Phe Val Gln Pro Asn Glu Thr Arg Thr Tyr
1605 1610 1615
ttt tgg aaa gtg cag cat cac atg gca ccc aca gaa gac gag ttt gac 4896
Phe Trp Lys Val Gln His His Met Ala Pro Thr Glu Asp Glu Phe Asp
1620 1625 1630
tgc aaa gcc tgg gcc tac ttt tct gat gtt gac ctg gaa aaa gat gtg 4944
Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val
1635 1640 1645
cac tca ggc ttg atc ggc ccc ctt ctg atc tgc cgc gcc aac acc ctg 4992
His Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Arg Ala Asn Thr Leu
1650 1655 1660
aac gct gct cac ggt aga caa gtg acc gtg caa gaa ttt gct ctg ttt 5040
Asn Ala Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe
1665 1670 1675 1680
ttc act att ttt gat gag aca aag agc tgg tac ttc act gaa aat gtg 5088
Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Val
1685 1690 1695
gaa agg aac tgc cgg gcc ccc tgc cac ctg cag atg gag gac ccc act 5136
Glu Arg Asn Cys Arg Ala Pro Cys His Leu Gln Met Glu Asp Pro Thr
1700 1705 1710
ctg aaa gaa aac tat cgc ttc cat gca atc aat ggc tat gtg atg gat 5184
Leu Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp
1715 1720 1725
aca ctc cct ggc tta gta atg gct cag aat caa agg atc cga tgg tat 5232
Thr Leu Pro Gly Leu Val Met Ala Gln Asn Gln Arg Ile Arg Trp Tyr
1730 1735 1740
ctg ctc agc atg ggc agc aat gaa aat atc cat tcg att cat ttt agc 5280
Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser
1745 1750 1755 1760
gga cac gtg ttc agt gta cgg aaa aag gag gag tat aaa atg gcc gtg 5328
Gly His Val Phe Ser Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Val
1765 1770 1775
tac aat ctc tat ccg ggt gtc ttt gag aca gtg gaa atg cta ccg tcc 5376
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser
1780 1785 1790
aaa gtt gga att tgg cga ata gaa tgc ctg att ggc gag cac ctg caa 5424
Lys Val Gly Ile Trp Arg Ile Glu Cys Leu Ile Gly Glu His Leu Gln
1795 1800 1805
gct ggg atg agc acg act ttc ctg gtg tac agc aag gag tgt cag gct 5472
Ala Gly Met Ser Thr Thr Phe Leu Val Tyr Ser Lys Glu Cys Gln Ala
1810 1815 1820
cca ctg gga atg gct tct gga cgc att aga gat ttt cag atc aca gct 5520
Pro Leu Gly Met Ala Ser Gly Arg Ile Arg Asp Phe Gln Ile Thr Ala
1825 1830 1835 1840
tca gga cag tat gga cag tgg gcc cca aag ctg gcc aga ctt cat tat 5568
Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr
1845 1850 1855
tcc gga tca atc aat gcc tgg agc acc aag gat ccc cac tcc tgg atc 5616
Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Asp Pro His Ser Trp Ile
1860 1865 1870
aag gtg gat ctg ttg gca cca atg atc att cac ggc atc atg acc cag 5664
Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Met Thr Gln
1875 1880 1885
ggt gcc cgt cag aag ttt tcc agc ctc tac atc tcc cag ttt atc atc 5712
Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile
1890 1895 1900
atg tac agt ctt gac ggg agg aac tgg cag agt tac cga ggg aat tcc 5760
Met Tyr Ser Leu Asp Gly Arg Asn Trp Gln Ser Tyr Arg Gly Asn Ser
1905 1910 1915 1920
acg ggc acc tta atg gtc ttc ttt ggc aat gtg gac gca tct ggg att 5808
Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ala Ser Gly Ile
1925 1930 1935
aaa cac aat att ttt aac cct ccg att gtg gct cgg tac atc cgt ttg 5856
Lys His Asn Ile Phe Asn Pro Pro Ile Val Ala Arg Tyr Ile Arg Leu
1940 1945 1950
cac cca aca cat tac agc atc cgc agc act ctt cgc atg gag ttg atg 5904
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met
1955 1960 1965
ggc tgt gat tta aac agt tgc agc atg ccc ctg gga atg cag aat aaa 5952
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Gln Asn Lys
1970 1975 1980
gcg ata tca gac tca cag atc acg gcc tcc tcc cac cta agc aat ata 6000
Ala Ile Ser Asp Ser Gln Ile Thr Ala Ser Ser His Leu Ser Asn Ile
1985 1990 1995 2000
ttt gcc acc tgg tct cct tca caa gcc cga ctt cac ctc cag ggg cgg 6048
Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu Gln Gly Arg
2005 2010 2015
acg aat gcc tgg cga ccc cgg gtg agc agc gca gag gag tgg ctg cag 6096
Thr Asn Ala Trp Arg Pro Arg Val Ser Ser Ala Glu Glu Trp Leu Gln
2020 2025 2030
gtg gac ctg cag aag acg gtg aag gtc aca ggc atc acc acc cag ggc 6144
Val Asp Leu Gln Lys Thr Val Lys Val Thr Gly Ile Thr Thr Gln Gly
2035 2040 2045
gtg aag tcc ctg ctc agc agc atg tat gtg aag gag ttc ctc gtg tcc 6192
Val Lys Ser Leu Leu Ser Ser Met Tyr Val Lys Glu Phe Leu Val Ser
2050 2055 2060
agt agt cag gac ggc cgc cgc tgg acc ctg ttt ctt cag gac ggc cac 6240
Ser Ser Gln Asp Gly Arg Arg Trp Thr Leu Phe Leu Gln Asp Gly His
2065 2070 2075 2080
acg aag gtt ttt cag ggc aat cag gac tcc tcc acc ccc gtg gtg aac 6288
Thr Lys Val Phe Gln Gly Asn Gln Asp Ser Ser Thr Pro Val Val Asn
2085 2090 2095
gct ctg gac ccc ccg ctg ttc acg cgc tac ctg agg atc cac ccc acg 6336
Ala Leu Asp Pro Pro Leu Phe Thr Arg Tyr Leu Arg Ile His Pro Thr
2100 2105 2110
agc tgg gcg cag cac atc gcc ctg agg ctc gag gtt cta gga tgt gag 6384
Ser Trp Ala Gln His Ile Ala Leu Arg Leu Glu Val Leu Gly Cys Glu
2115 2120 2125
gca cag gat ctc tac tga 6402
Ala Gln Asp Leu Tyr
2130
<210> 30
<211> 2133
<212> PRT
<213> Porcine
<400> 30
Met Gln Leu Glu Leu Ser Thr Cys Val Phe Leu Cys Leu Leu Pro Leu
1 5 10 15
Gly Phe Ser Ala Ile Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Arg Gln Ser Glu Leu Leu Arg Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Ala Thr Ala Pro Gly Ala Leu Pro Leu Gly Pro Ser Val
50 55 60
Leu Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp Gln Leu Phe Ser
65 70 75 80
Val Ala Arg Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Gln Ala Glu Val Tyr Asp Thr Val Val Val Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Phe Trp Lys Ser
115 120 125
Ser Glu Gly Ala Glu Tyr Glu Asp His Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Leu Pro Gly Lys Ser Gln Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Thr Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Thr Arg Glu Arg
195 200 205
Thr Gln Asn Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Ala Arg Asn Asp Ser Trp Thr Arg Ala Met
225 230 235 240
Asp Pro Ala Pro Ala Arg Ala Gln Pro Ala Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Lys Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Ser Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg His His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Leu Thr Phe Leu Thr Ala Gln Thr Phe Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His His
325 330 335
His Gly Gly Met Glu Ala His Val Arg Val Glu Ser Cys Ala Glu Glu
340 345 350
Pro Gln Leu Arg Arg Lys Ala Asp Glu Glu Glu Asp Tyr Asp Asp Asn
355 360 365
Leu Tyr Asp Ser Asp Met Asp Val Val Arg Leu Asp Gly Asp Asp Val
370 375 380
Ser Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr
385 390 395 400
Trp Val His Tyr Ile Ser Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro
405 410 415
Ala Val Pro Ser Pro Ser Asp Arg Ser Tyr Lys Ser Leu Tyr Leu Asn
420 425 430
Ser Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Ala Arg Phe Val
435 440 445
Ala Tyr Thr Asp Val Thr Phe Lys Thr Arg Lys Ala Ile Pro Tyr Glu
450 455 460
Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu
465 470 475 480
Leu Ile Ile Phe Lys Asn Lys Ala Ser Arg Pro Tyr Asn Ile Tyr Pro
485 490 495
His Gly Ile Thr Asp Val Ser Ala Leu His Pro Gly Arg Leu Leu Lys
500 505 510
Gly Trp Lys His Leu Lys Asp Met Pro Ile Leu Pro Gly Glu Thr Phe
515 520 525
Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp
530 535 540
Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Ser Ile Asn Leu Glu Lys
545 550 555 560
Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu
565 570 575
Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn Val
580 585 590
Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Ala Glu
595 600 605
Asn Ile Gln Arg Phe Leu Pro Asn Pro Asp Gly Leu Gln Pro Gln Asp
610 615 620
Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
625 630 635 640
Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp
645 650 655
Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe
660 665 670
Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr
675 680 685
Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro
690 695 700
Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Leu Arg Asn Arg Gly
705 710 715 720
Met Thr Ala Leu Leu Lys Val Tyr Ser Cys Asp Arg Asp Ile Gly Asp
725 730 735
Tyr Tyr Asp Asn Thr Tyr Glu Asp Ile Pro Gly Phe Leu Leu Ser Gly
740 745 750
Lys Asn Val Ile Glu Pro Arg Ser Phe Ala Gln Asn Ser Arg Pro Pro
755 760 765
Ser Ala Ser Gln Lys Gln Phe Gln Thr Ile Thr Ser Pro Glu Asp Asp
770 775 780
Val Glu Leu Asp Pro Gln Ser Gly Glu Arg Thr Gln Ala Leu Glu Glu
785 790 795 800
Leu Ser Val Pro Ser Gly Asp Gly Ser Met Leu Leu Gly Gln Asn Pro
805 810 815
Ala Pro His Gly Ser Ser Ser Ser Asp Leu Gln Glu Ala Arg Asn Glu
820 825 830
Ala Asp Asp Tyr Leu Pro Gly Ala Arg Glu Arg Gly Thr Ala Pro Ser
835 840 845
Ala Ala Ala Arg Leu Arg Pro Glu Leu His His Ser Ala Glu Arg Val
850 855 860
Leu Thr Pro Glu Pro Glu Lys Glu Leu Lys Lys Leu Asp Ser Lys Met
865 870 875 880
Ser Ser Ser Ser Asp Leu Leu Lys Thr Ser Pro Thr Ile Pro Ser Asp
885 890 895
Thr Leu Ser Ala Glu Thr Glu Arg Thr His Ser Leu Gly Pro Pro His
900 905 910
Pro Gln Val Asn Phe Arg Ser Gln Leu Gly Ala Ile Val Leu Gly Lys
915 920 925
Asn Ser Ser His Phe Ile Gly Ala Gly Val Pro Leu Gly Ser Thr Glu
930 935 940
Glu Asp His Glu Ser Ser Leu Gly Glu Asn Val Ser Pro Val Glu Ser
945 950 955 960
Asp Gly Ile Phe Glu Lys Glu Arg Ala His Gly Pro Ala Ser Leu Thr
965 970 975
Lys Asp Asp Val Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
980 985 990
Lys Ala Arg Val Tyr Leu Lys Thr Asn Arg Lys Ile His Ile Asp Asp
995 1000 1005
Ala Ala Leu Leu Thr Glu Asn Arg Ala Ser Ala Thr Phe Met Asp Lys
1010 1015 1020
Asn Thr Thr Ala Ser Gly Leu Asn His Val Ser Asn Trp Ile Lys Gly
1025 1030 1035 1040
Pro Leu Gly Lys Asn Pro Leu Ser Ser Glu Arg Gly Pro Ser Pro Glu
1045 1050 1055
Leu Leu Thr Ser Ser Gly Ser Gly Lys Ser Val Lys Gly Gln Ser Ser
1060 1065 1070
Gly Gln Gly Arg Ile Arg Val Ala Val Glu Glu Glu Glu Leu Ser Lys
1075 1080 1085
Gly Lys Glu Met Met Leu Pro Asn Ser Glu Leu Thr Phe Leu Thr Asn
1090 1095 1100
Ser Ala Asp Val Gln Gly Asn Asp Thr His Ser Gln Gly Lys Lys Ser
1105 1110 1115 1120
Arg Glu Glu Met Glu Arg Arg Glu Lys Leu Val Gln Glu Lys Val Asp
1125 1130 1135
Leu Pro Gln Val Tyr Thr Ala Thr Gly Thr Lys Asn Phe Leu Arg Asn
1140 1145 1150
Ile Phe His Gln Ser Thr Glu Pro Ser Val Glu Gly Phe Asp Gly Gly
1155 1160 1165
Ser His Ala Pro Val Pro Gln Asp Ser Arg Ser Leu Asn Asp Ser Ala
1170 1175 1180
Glu Arg Ala Glu Thr His Ile Ala His Phe Ser Ala Ile Arg Glu Glu
1185 1190 1195 1200
Ala Pro Leu Glu Ala Pro Gly Asn Arg Thr Gly Pro Gly Pro Arg Ser
1205 1210 1215
Ala Val Pro Arg Arg Val Lys Gln Ser Leu Lys Gln Ile Arg Leu Pro
1220 1225 1230
Leu Glu Glu Ile Lys Pro Glu Arg Gly Val Val Leu Asn Ala Thr Ser
1235 1240 1245
Thr Arg Trp Ser Glu Ser Ser Pro Ile Leu Gln Gly Ala Lys Arg Asn
1250 1255 1260
Asn Leu Ser Leu Pro Phe Leu Thr Leu Glu Met Ala Gly Gly Gln Gly
1265 1270 1275 1280
Lys Ile Ser Ala Leu Gly Lys Ser Ala Ala Gly Pro Leu Ala Ser Gly
1285 1290 1295
Lys Leu Glu Lys Ala Val Leu Ser Ser Ala Gly Leu Ser Glu Ala Ser
1300 1305 1310
Gly Lys Ala Glu Phe Leu Pro Lys Val Arg Val His Arg Glu Asp Leu
1315 1320 1325
Leu Pro Gln Lys Thr Ser Asn Val Ser Cys Ala His Gly Asp Leu Gly
1330 1335 1340
Gln Glu Ile Phe Leu Gln Lys Thr Arg Gly Pro Val Asn Leu Asn Lys
1345 1350 1355 1360
Val Asn Arg Pro Gly Arg Thr Pro Ser Lys Leu Leu Gly Pro Pro Met
1365 1370 1375
Pro Lys Glu Trp Glu Ser Leu Glu Lys Ser Pro Lys Ser Thr Ala Leu
1380 1385 1390
Arg Thr Lys Asp Ile Ile Ser Leu Pro Leu Asp Arg His Glu Ser Asn
1395 1400 1405
His Ser Ile Ala Ala Lys Asn Glu Gly Gln Ala Glu Thr Gln Arg Glu
1410 1415 1420
Ala Ala Trp Thr Lys Gln Gly Gly Pro Gly Arg Leu Cys Ala Pro Lys
1425 1430 1435 1440
Pro Pro Val Leu Arg Arg His Gln Arg Asp Ile Ser Leu Pro Thr Phe
1445 1450 1455
Gln Pro Glu Glu Asp Lys Met Asp Tyr Asp Asp Ile Phe Ser Thr Glu
1460 1465 1470
Thr Lys Gly Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Asp
1475 1480 1485
Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala Ala Val
1490 1495 1500
Glu Gln Leu Trp Asp Tyr Gly Met Ser Glu Ser Pro Arg Ala Leu Arg
1505 1510 1515 1520
Asn Arg Ala Gln Asn Gly Glu Val Pro Arg Phe Lys Lys Val Val Phe
1525 1530 1535
Arg Glu Phe Ala Asp Gly Ser Phe Thr Gln Pro Ser Tyr Arg Gly Glu
1540 1545 1550
Leu Asn Lys His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val
1555 1560 1565
Glu Asp Asn Ile Met Val Thr Phe Lys Asn Gln Ala Ser Arg Pro Tyr
1570 1575 1580
Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Pro Asp Asp Gln Glu Gln Gly
1585 1590 1595 1600
Ala Glu Pro Arg His Asn Phe Val Gln Pro Asn Glu Thr Arg Thr Tyr
1605 1610 1615
Phe Trp Lys Val Gln His His Met Ala Pro Thr Glu Asp Glu Phe Asp
1620 1625 1630
Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val
1635 1640 1645
His Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Arg Ala Asn Thr Leu
1650 1655 1660
Asn Ala Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe
1665 1670 1675 1680
Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Val
1685 1690 1695
Glu Arg Asn Cys Arg Ala Pro Cys His Leu Gln Met Glu Asp Pro Thr
1700 1705 1710
Leu Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp
1715 1720 1725
Thr Leu Pro Gly Leu Val Met Ala Gln Asn Gln Arg Ile Arg Trp Tyr
1730 1735 1740
Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser
1745 1750 1755 1760
Gly His Val Phe Ser Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Val
1765 1770 1775
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser
1780 1785 1790
Lys Val Gly Ile Trp Arg Ile Glu Cys Leu Ile Gly Glu His Leu Gln
1795 1800 1805
Ala Gly Met Ser Thr Thr Phe Leu Val Tyr Ser Lys Glu Cys Gln Ala
1810 1815 1820
Pro Leu Gly Met Ala Ser Gly Arg Ile Arg Asp Phe Gln Ile Thr Ala
1825 1830 1835 1840
Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr
1845 1850 1855
Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Asp Pro His Ser Trp Ile
1860 1865 1870
Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Met Thr Gln
1875 1880 1885
Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile
1890 1895 1900
Met Tyr Ser Leu Asp Gly Arg Asn Trp Gln Ser Tyr Arg Gly Asn Ser
1905 1910 1915 1920
Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ala Ser Gly Ile
1925 1930 1935
Lys His Asn Ile Phe Asn Pro Pro Ile Val Ala Arg Tyr Ile Arg Leu
1940 1945 1950
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met
1955 1960 1965
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Gln Asn Lys
1970 1975 1980
Ala Ile Ser Asp Ser Gln Ile Thr Ala Ser Ser His Leu Ser Asn Ile
1985 1990 1995 2000
Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu Gln Gly Arg
2005 2010 2015
Thr Asn Ala Trp Arg Pro Arg Val Ser Ser Ala Glu Glu Trp Leu Gln
2020 2025 2030
Val Asp Leu Gln Lys Thr Val Lys Val Thr Gly Ile Thr Thr Gln Gly
2035 2040 2045
Val Lys Ser Leu Leu Ser Ser Met Tyr Val Lys Glu Phe Leu Val Ser
2050 2055 2060
Ser Ser Gln Asp Gly Arg Arg Trp Thr Leu Phe Leu Gln Asp Gly His
2065 2070 2075 2080
Thr Lys Val Phe Gln Gly Asn Gln Asp Ser Ser Thr Pro Val Val Asn
2085 2090 2095
Ala Leu Asp Pro Pro Leu Phe Thr Arg Tyr Leu Arg Ile His Pro Thr
2100 2105 2110
Ser Trp Ala Gln His Ile Ala Leu Arg Leu Glu Val Leu Gly Cys Glu
2115 2120 2125
Ala Gln Asp Leu Tyr
2130
<210> 31
<211> 19
<212> PRT
<213> Homo sapiens
<400> 31
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Cys Phe Ser
<210> 32
<211> 24
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:linker
<400> 32
Ser Phe Ala Gln Asn Ser Arg Pro Pro Ser Ala Ser Ala Pro Lys Pro
1 5 10 15
Pro Val Leu Arg Arg His Gln Arg
20
<210> 33
<211> 105
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:linker
<400> 33
gtcattgaac ctaggagctt tgcccagaat tcaagacccc ctagtgcgag cgctccaaag 60
cctccggtcc tgcgacggca tcagagggac ataagccttc ctact 105
<210> 34
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 34
gaggaaaacc agatgatgtc a 21
<210> 35
<211> 60
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 35
ctttggagcg ctcgcactag ggggtcttga attctgggca aagctcctag gttcaatgac 60
<210> 36
<211> 66
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence:oligonucleotide
primer
<400> 36
cctagtgcga gcgctccaaa gcctccggtc ctgcgacggc atcagaggga cataagcctt 60
cctact 66
<210> 37
<211> 4404
<212> DNA
<213> Porcine
<220>
<221> CDS
<222> (1)..(4401)
<400> 37
atg cag cta gag ctc tcc acc tgt gtc ttt ctg tgt ctc ttg cca ctc 48
Met Gln Leu Glu Leu Ser Thr Cys Val Phe Leu Cys Leu Leu Pro Leu
1 5 10 15
ggc ttt agt gcc atc agg aga tac tac ctg ggc gca gtg gaa ctg tcc 96
Gly Phe Ser Ala Ile Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
tgg gac tac cgg caa agt gaa ctc ctc cgt gag ctg cac gtg gac acc 144
Trp Asp Tyr Arg Gln Ser Glu Leu Leu Arg Glu Leu His Val Asp Thr
35 40 45
aga ttt cct gct aca gcg cca gga gct ctt ccg ttg ggc ccg tca gtc 192
Arg Phe Pro Ala Thr Ala Pro Gly Ala Leu Pro Leu Gly Pro Ser Val
50 55 60
ctg tac aaa aag act gtg ttc gta gag ttc acg gat caa ctt ttc agc 240
Leu Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp Gln Leu Phe Ser
65 70 75 80
gtt gcc agg ccc agg cca cca tgg atg ggt ctg ctg ggt cct acc atc 288
Val Ala Arg Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
cag gct gag gtt tac gac acg gtg gtc gtt acc ctg aag aac atg gct 336
Gln Ala Glu Val Tyr Asp Thr Val Val Val Thr Leu Lys Asn Met Ala
100 105 110
tct cat ccc gtt agt ctt cac gct gtc ggc gtc tcc ttc tgg aaa tct 384
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Phe Trp Lys Ser
115 120 125
tcc gaa ggc gct gaa tat gag gat cac acc agc caa agg gag aag gaa 432
Ser Glu Gly Ala Glu Tyr Glu Asp His Thr Ser Gln Arg Glu Lys Glu
130 135 140
gac gat aaa gtc ctt ccc ggt aaa agc caa acc tac gtc tgg cag gtc 480
Asp Asp Lys Val Leu Pro Gly Lys Ser Gln Thr Tyr Val Trp Gln Val
145 150 155 160
ctg aaa gaa aat ggt cca aca gcc tct gac cca cca tgt ctt acc tac 528
Leu Lys Glu Asn Gly Pro Thr Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
tca tac ctg tct cac gtg gac ctg gtg aaa gac ctg aat tcg ggc ctc 576
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
att gga gcc ctg ctg gtt tgt aga gaa ggg agt ctg acc aga gaa agg 624
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Thr Arg Glu Arg
195 200 205
acc cag aac ctg cac gaa ttt gta cta ctt ttt gct gtc ttt gat gaa 672
Thr Gln Asn Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
ggg aaa agt tgg cac tca gca aga aat gac tcc tgg aca cgg gcc atg 720
Gly Lys Ser Trp His Ser Ala Arg Asn Asp Ser Trp Thr Arg Ala Met
225 230 235 240
gat ccc gca cct gcc agg gcc cag cct gca atg cac aca gtc aat ggc 768
Asp Pro Ala Pro Ala Arg Ala Gln Pro Ala Met His Thr Val Asn Gly
245 250 255
tat gtc aac agg tct ctg cca ggt ctg atc gga tgt cat aag aaa tca 816
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Lys Lys Ser
260 265 270
gtc tac tgg cac gtg att gga atg ggc acc agc ccg gaa gtg cac tcc 864
Val Tyr Trp His Val Ile Gly Met Gly Thr Ser Pro Glu Val His Ser
275 280 285
att ttt ctt gaa ggc cac acg ttt ctc gtg agg cac cat cgc cag gct 912
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg His His Arg Gln Ala
290 295 300
tcc ttg gag atc tcg cca cta act ttc ctc act gct cag aca ttc ctg 960
Ser Leu Glu Ile Ser Pro Leu Thr Phe Leu Thr Ala Gln Thr Phe Leu
305 310 315 320
atg gac ctt ggc cag ttc cta ctg ttt tgt cat atc tct tcc cac cac 1008
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His His
325 330 335
cat ggt ggc atg gag gct cac gtc aga gta gaa agc tgc gcc gag gag 1056
His Gly Gly Met Glu Ala His Val Arg Val Glu Ser Cys Ala Glu Glu
340 345 350
ccc cag ctg cgg agg aaa gct gat gaa gag gaa gat tat gat gac aat 1104
Pro Gln Leu Arg Arg Lys Ala Asp Glu Glu Glu Asp Tyr Asp Asp Asn
355 360 365
ttg tac gac tcg gac atg gac gtg gtc cgg ctc gat ggt gac gac gtg 1152
Leu Tyr Asp Ser Asp Met Asp Val Val Arg Leu Asp Gly Asp Asp Val
370 375 380
tct ccc ttt atc caa atc cgc tcg gtt gcc aag aag cat ccc aaa acc 1200
Ser Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr
385 390 395 400
tgg gtg cac tac atc tct gca gag gag gag gac tgg gac tac gcc ccc 1248
Trp Val His Tyr Ile Ser Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro
405 410 415
gcg gtc ccc agc ccc agt gac aga agt tat aaa agt ctc tac ttg aac 1296
Ala Val Pro Ser Pro Ser Asp Arg Ser Tyr Lys Ser Leu Tyr Leu Asn
420 425 430
agt ggt cct cag cga att ggt agg aaa tac aaa aaa gct cga ttc gtc 1344
Ser Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Ala Arg Phe Val
435 440 445
gct tac acg gat gta aca ttt aag act cgt aaa gct att ccg tat gaa 1392
Ala Tyr Thr Asp Val Thr Phe Lys Thr Arg Lys Ala Ile Pro Tyr Glu
450 455 460
tca gga atc ctg gga cct tta ctt tat gga gaa gtt gga gac aca ctt 1440
Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu
465 470 475 480
ttg att ata ttt aag aat aaa gcg agc cga cca tat aac atc tac cct 1488
Leu Ile Ile Phe Lys Asn Lys Ala Ser Arg Pro Tyr Asn Ile Tyr Pro
485 490 495
cat gga atc act gat gtc agc gct ttg cac cca ggg aga ctt cta aaa 1536
His Gly Ile Thr Asp Val Ser Ala Leu His Pro Gly Arg Leu Leu Lys
500 505 510
ggt tgg aaa cat ttg aaa gac atg cca att ctg cca gga gag act ttc 1584
Gly Trp Lys His Leu Lys Asp Met Pro Ile Leu Pro Gly Glu Thr Phe
515 520 525
aag tat aaa tgg aca gtg act gtg gaa gat ggg cca acc aag tcc gat 1632
Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp
530 535 540
cct cgg tgc ctg acc cgc tac tac tcg agc tcc att aat cta gag aaa 1680
Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Ser Ile Asn Leu Glu Lys
545 550 555 560
gat ctg gct tcg gga ctc att ggc cct ctc ctc atc tgc tac aaa gaa 1728
Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu
565 570 575
tct gta gac caa aga gga aac cag atg atg tca gac aag aga aac gtc 1776
Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn Val
580 585 590
atc ctg ttt tct gta ttc gat gag aat caa agc tgg tac ctc gca gag 1824
Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Ala Glu
595 600 605
aat att cag cgc ttc ctc ccc aat ccg gat gga tta cag ccc cag gat 1872
Asn Ile Gln Arg Phe Leu Pro Asn Pro Asp Gly Leu Gln Pro Gln Asp
610 615 620
cca gag ttc caa gct tct aac atc atg cac agc atc aat ggc tat gtt 1920
Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
625 630 635 640
ttt gat agc ttg cag ctg tcg gtt tgt ttg cac gag gtg gca tac tgg 1968
Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp
645 650 655
tac att cta agt gtt gga gca cag acg gac ttc ctc tcc gtc ttc ttc 2016
Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe
660 665 670
tct ggc tac acc ttc aaa cac aaa atg gtc tat gaa gac aca ctc acc 2064
Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr
675 680 685
ctg ttc ccc ttc tca gga gaa acg gtc ttc atg tca atg gaa aac cca 2112
Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro
690 695 700
ggt ctc tgg gtc ctt ggg tgc cac aac tca gac ttg cgg aac aga ggg 2160
Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Leu Arg Asn Arg Gly
705 710 715 720
atg aca gcc tta ctg aag gtg tat agt tgt gac agg gac att ggt gat 2208
Met Thr Ala Leu Leu Lys Val Tyr Ser Cys Asp Arg Asp Ile Gly Asp
725 730 735
tat tat gac aac act tat gaa gat att cca ggc ttc ttg ctg agt gga 2256
Tyr Tyr Asp Asn Thr Tyr Glu Asp Ile Pro Gly Phe Leu Leu Ser Gly
740 745 750
aag aat gtc att gaa cct agg agc ttt gcc cag aat tca aga ccc cct 2304
Lys Asn Val Ile Glu Pro Arg Ser Phe Ala Gln Asn Ser Arg Pro Pro
755 760 765
agt gcg agc gct cca aag cct ccg gtc ctg cga cgg cat cag agg gac 2352
Ser Ala Ser Ala Pro Lys Pro Pro Val Leu Arg Arg His Gln Arg Asp
770 775 780
ata agc ctt cct act ttt cag ccg gag gaa gac aaa atg gac tat gat 2400
Ile Ser Leu Pro Thr Phe Gln Pro Glu Glu Asp Lys Met Asp Tyr Asp
785 790 795 800
gat atc ttc tca act gaa acg aag gga gaa gat ttt gac att tac ggt 2448
Asp Ile Phe Ser Thr Glu Thr Lys Gly Glu Asp Phe Asp Ile Tyr Gly
805 810 815
gag gat gaa aat cag gac cct cgc agc ttt cag aag aga acc cga cac 2496
Glu Asp Glu Asn Gln Asp Pro Arg Ser Phe Gln Lys Arg Thr Arg His
820 825 830
tat ttc att gct gcg gtg gag cag ctc tgg gat tac ggg atg agc gaa 2544
Tyr Phe Ile Ala Ala Val Glu Gln Leu Trp Asp Tyr Gly Met Ser Glu
835 840 845
tcc ccc cgg gcg cta aga aac agg gct cag aac gga gag gtg cct cgg 2592
Ser Pro Arg Ala Leu Arg Asn Arg Ala Gln Asn Gly Glu Val Pro Arg
850 855 860
ttc aag aag gtg gtc ttc cgg gaa ttt gct gac ggc tcc ttc acg cag 2640
Phe Lys Lys Val Val Phe Arg Glu Phe Ala Asp Gly Ser Phe Thr Gln
865 870 875 880
ccg tcg tac cgc ggg gaa ctc aac aaa cac ttg ggg ctc ttg gga ccc 2688
Pro Ser Tyr Arg Gly Glu Leu Asn Lys His Leu Gly Leu Leu Gly Pro
885 890 895
tac atc aga gcg gaa gtt gaa gac aac atc atg gta act ttc aaa aac 2736
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys Asn
900 905 910
cag gcg tct cgt ccc tat tcc ttc tac tcg agc ctt att tct tat ccg 2784
Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Pro
915 920 925
gat gat cag gag caa ggg gca gaa cct cga cac aac ttc gtc cag cca 2832
Asp Asp Gln Glu Gln Gly Ala Glu Pro Arg His Asn Phe Val Gln Pro
930 935 940
aat gaa acc aga act tac ttt tgg aaa gtg cag cat cac atg gca ccc 2880
Asn Glu Thr Arg Thr Tyr Phe Trp Lys Val Gln His His Met Ala Pro
945 950 955 960
aca gaa gac gag ttt gac tgc aaa gcc tgg gcc tac ttt tct gat gtt 2928
Thr Glu Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val
965 970 975
gac ctg gaa aaa gat gtg cac tca ggc ttg atc ggc ccc ctt ctg atc 2976
Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu Ile
980 985 990
tgc cgc gcc aac acc ctg aac gct gct cac ggt aga caa gtg acc gtg 3024
Cys Arg Ala Asn Thr Leu Asn Ala Ala His Gly Arg Gln Val Thr Val
995 1000 1005
caa gaa ttt gct ctg ttt ttc act att ttt gat gag aca aag agc tgg 3072
Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp
1010 1015 1020
tac ttc act gaa aat gtg gaa agg aac tgc cgg gcc ccc tgc cat ctg 3120
Tyr Phe Thr Glu Asn Val Glu Arg Asn Cys Arg Ala Pro Cys His Leu
1025 1030 1035 1040
cag atg gag gac ccc act ctg aaa gaa aac tat cgc ttc cat gca atc 3168
Gln Met Glu Asp Pro Thr Leu Lys Glu Asn Tyr Arg Phe His Ala Ile
1045 1050 1055
aat ggc tat gtg atg gat aca ctc cct ggc tta gta atg gct cag aat 3216
Asn Gly Tyr Val Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asn
1060 1065 1070
caa agg atc cga tgg tat ctg ctc agc atg ggc agc aat gaa aat atc 3264
Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile
1075 1080 1085
cat tcg att cat ttt agc gga cac gtg ttc agt gta cgg aaa aag gag 3312
His Ser Ile His Phe Ser Gly His Val Phe Ser Val Arg Lys Lys Glu
1090 1095 1100
gag tat aaa atg gcc gtg tac aat ctc tat ccg ggt gtc ttt gag aca 3360
Glu Tyr Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr
1105 1110 1115 1120
gtg gaa atg cta ccg tcc aaa gtt gga att tgg cga ata gaa tgc ctg 3408
Val Glu Met Leu Pro Ser Lys Val Gly Ile Trp Arg Ile Glu Cys Leu
1125 1130 1135
att ggc gag cac ctg caa gct ggg atg agc acg act ttc ctg gtg tac 3456
Ile Gly Glu His Leu Gln Ala Gly Met Ser Thr Thr Phe Leu Val Tyr
1140 1145 1150
agc aag gag tgt cag gct cca ctg gga atg gct tct gga cgc att aga 3504
Ser Lys Glu Cys Gln Ala Pro Leu Gly Met Ala Ser Gly Arg Ile Arg
1155 1160 1165
gat ttt cag atc aca gct tca gga cag tat gga cag tgg gcc cca aag 3552
Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys
1170 1175 1180
ctg gcc aga ctt cat tat tcc gga tca atc aat gcc tgg agc acc aag 3600
Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys
1185 1190 1195 1200
gat ccc cac tcc tgg atc aag gtg gat ctg ttg gca cca atg atc att 3648
Asp Pro His Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile
1205 1210 1215
cac ggc atc atg acc cag ggt gcc cgt cag aag ttt tcc agc ctc tac 3696
His Gly Ile Met Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr
1220 1225 1230
atc tcc cag ttt atc atc atg tac agt ctt gac ggg agg aac tgg cag 3744
Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Arg Asn Trp Gln
1235 1240 1245
agt tac cga ggg aat tcc acg ggc acc tta atg gtc ttc ttt ggc aat 3792
Ser Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn
1250 1255 1260
gtg gac gca tct ggg att aaa cac aat att ttt aac cct ccg att gtg 3840
Val Asp Ala Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile Val
1265 1270 1275 1280
gct cgg tac atc cgt ttg cac cca aca cat tac agc atc cgc agc act 3888
Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser Thr
1285 1290 1295
ctt cgc atg gag ttg atg ggc tgt gat tta aac agt tgc agc atg ccc 3936
Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro
1300 1305 1310
ctg gga atg cag aat aaa gcg ata tca gac tca cag atc acg gcc tcc 3984
Leu Gly Met Gln Asn Lys Ala Ile Ser Asp Ser Gln Ile Thr Ala Ser
1315 1320 1325
tcc cac cta agc aat ata ttt gcc acc tgg tct cct tca caa gcc cga 4032
Ser His Leu Ser Asn Ile Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg
1330 1335 1340
ctt cac ctc cag ggg cgg acg aat gcc tgg cga ccc cgg gtg agc agc 4080
Leu His Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Arg Val Ser Ser
1345 1350 1355 1360
gca gag gag tgg ctg cag gtg gac ctg cag aag acg gtg aag gtc aca 4128
Ala Glu Glu Trp Leu Gln Val Asp Leu Gln Lys Thr Val Lys Val Thr
1365 1370 1375
ggc atc acc acc cag ggc gtg aag tcc ctg ctc agc agc atg tat gtg 4176
Gly Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Ser Ser Met Tyr Val
1380 1385 1390
aag gag ttc ctc gtg tcc agt agt cag gac ggc cgc cgc tgg acc ctg 4224
Lys Glu Phe Leu Val Ser Ser Ser Gln Asp Gly Arg Arg Trp Thr Leu
1395 1400 1405
ttt ctt cag gac ggc cac acg aag gtt ttt cag ggc aat cag gac tcc 4272
Phe Leu Gln Asp Gly His Thr Lys Val Phe Gln Gly Asn Gln Asp Ser
1410 1415 1420
tcc acc ccc gtg gtg aac gct ctg gac ccc ccg ctg ttc acg cgc tac 4320
Ser Thr Pro Val Val Asn Ala Leu Asp Pro Pro Leu Phe Thr Arg Tyr
1425 1430 1435 1440
ctg agg atc cac ccc acg agc tgg gcg cag cac atc gcc ctg agg ctc 4368
Leu Arg Ile His Pro Thr Ser Trp Ala Gln His Ile Ala Leu Arg Leu
1445 1450 1455
gag gtt cta gga tgt gag gca cag gat ctc tac tga 4404
Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
1460 1465
<210> 38
<211> 1467
<212> PRT
<213> Porcine
<400> 38
Met Gln Leu Glu Leu Ser Thr Cys Val Phe Leu Cys Leu Leu Pro Leu
1 5 10 15
Gly Phe Ser Ala Ile Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Arg Gln Ser Glu Leu Leu Arg Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Ala Thr Ala Pro Gly Ala Leu Pro Leu Gly Pro Ser Val
50 55 60
Leu Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp Gln Leu Phe Ser
65 70 75 80
Val Ala Arg Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Gln Ala Glu Val Tyr Asp Thr Val Val Val Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Phe Trp Lys Ser
115 120 125
Ser Glu Gly Ala Glu Tyr Glu Asp His Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Leu Pro Gly Lys Ser Gln Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Thr Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Thr Arg Glu Arg
195 200 205
Thr Gln Asn Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Ala Arg Asn Asp Ser Trp Thr Arg Ala Met
225 230 235 240
Asp Pro Ala Pro Ala Arg Ala Gln Pro Ala Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Lys Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Ser Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg His His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Leu Thr Phe Leu Thr Ala Gln Thr Phe Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His His
325 330 335
His Gly Gly Met Glu Ala His Val Arg Val Glu Ser Cys Ala Glu Glu
340 345 350
Pro Gln Leu Arg Arg Lys Ala Asp Glu Glu Glu Asp Tyr Asp Asp Asn
355 360 365
Leu Tyr Asp Ser Asp Met Asp Val Val Arg Leu Asp Gly Asp Asp Val
370 375 380
Ser Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr
385 390 395 400
Trp Val His Tyr Ile Ser Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro
405 410 415
Ala Val Pro Ser Pro Ser Asp Arg Ser Tyr Lys Ser Leu Tyr Leu Asn
420 425 430
Ser Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Ala Arg Phe Val
435 440 445
Ala Tyr Thr Asp Val Thr Phe Lys Thr Arg Lys Ala Ile Pro Tyr Glu
450 455 460
Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu
465 470 475 480
Leu Ile Ile Phe Lys Asn Lys Ala Ser Arg Pro Tyr Asn Ile Tyr Pro
485 490 495
His Gly Ile Thr Asp Val Ser Ala Leu His Pro Gly Arg Leu Leu Lys
500 505 510
Gly Trp Lys His Leu Lys Asp Met Pro Ile Leu Pro Gly Glu Thr Phe
515 520 525
Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp
530 535 540
Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Ser Ile Asn Leu Glu Lys
545 550 555 560
Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu
565 570 575
Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn Val
580 585 590
Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Ala Glu
595 600 605
Asn Ile Gln Arg Phe Leu Pro Asn Pro Asp Gly Leu Gln Pro Gln Asp
610 615 620
Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
625 630 635 640
Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp
645 650 655
Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe
660 665 670
Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr
675 680 685
Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro
690 695 700
Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Leu Arg Asn Arg Gly
705 710 715 720
Met Thr Ala Leu Leu Lys Val Tyr Ser Cys Asp Arg Asp Ile Gly Asp
725 730 735
Tyr Tyr Asp Asn Thr Tyr Glu Asp Ile Pro Gly Phe Leu Leu Ser Gly
740 745 750
Lys Asn Val Ile Glu Pro Arg Ser Phe Ala Gln Asn Ser Arg Pro Pro
755 760 765
Ser Ala Ser Ala Pro Lys Pro Pro Val Leu Arg Arg His Gln Arg Asp
770 775 780
Ile Ser Leu Pro Thr Phe Gln Pro Glu Glu Asp Lys Met Asp Tyr Asp
785 790 795 800
Asp Ile Phe Ser Thr Glu Thr Lys Gly Glu Asp Phe Asp Ile Tyr Gly
805 810 815
Glu Asp Glu Asn Gln Asp Pro Arg Ser Phe Gln Lys Arg Thr Arg His
820 825 830
Tyr Phe Ile Ala Ala Val Glu Gln Leu Trp Asp Tyr Gly Met Ser Glu
835 840 845
Ser Pro Arg Ala Leu Arg Asn Arg Ala Gln Asn Gly Glu Val Pro Arg
850 855 860
Phe Lys Lys Val Val Phe Arg Glu Phe Ala Asp Gly Ser Phe Thr Gln
865 870 875 880
Pro Ser Tyr Arg Gly Glu Leu Asn Lys His Leu Gly Leu Leu Gly Pro
885 890 895
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys Asn
900 905 910
Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Pro
915 920 925
Asp Asp Gln Glu Gln Gly Ala Glu Pro Arg His Asn Phe Val Gln Pro
930 935 940
Asn Glu Thr Arg Thr Tyr Phe Trp Lys Val Gln His His Met Ala Pro
945 950 955 960
Thr Glu Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val
965 970 975
Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu Ile
980 985 990
Cys Arg Ala Asn Thr Leu Asn Ala Ala His Gly Arg Gln Val Thr Val
995 1000 1005
Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp
1010 1015 1020
Tyr Phe Thr Glu Asn Val Glu Arg Asn Cys Arg Ala Pro Cys His Leu
1025 1030 1035 1040
Gln Met Glu Asp Pro Thr Leu Lys Glu Asn Tyr Arg Phe His Ala Ile
1045 1050 1055
Asn Gly Tyr Val Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asn
1060 1065 1070
Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile
1075 1080 1085
His Ser Ile His Phe Ser Gly His Val Phe Ser Val Arg Lys Lys Glu
1090 1095 1100
Glu Tyr Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr
1105 1110 1115 1120
Val Glu Met Leu Pro Ser Lys Val Gly Ile Trp Arg Ile Glu Cys Leu
1125 1130 1135
Ile Gly Glu His Leu Gln Ala Gly Met Ser Thr Thr Phe Leu Val Tyr
1140 1145 1150
Ser Lys Glu Cys Gln Ala Pro Leu Gly Met Ala Ser Gly Arg Ile Arg
1155 1160 1165
Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys
1170 1175 1180
Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys
1185 1190 1195 1200
Asp Pro His Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile
1205 1210 1215
His Gly Ile Met Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr
1220 1225 1230
Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Arg Asn Trp Gln
1235 1240 1245
Ser Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn
1250 1255 1260
Val Asp Ala Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile Val
1265 1270 1275 1280
Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser Thr
1285 1290 1295
Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro
1300 1305 1310
Leu Gly Met Gln Asn Lys Ala Ile Ser Asp Ser Gln Ile Thr Ala Ser
1315 1320 1325
Ser His Leu Ser Asn Ile Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg
1330 1335 1340
Leu His Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Arg Val Ser Ser
1345 1350 1355 1360
Ala Glu Glu Trp Leu Gln Val Asp Leu Gln Lys Thr Val Lys Val Thr
1365 1370 1375
Gly Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Ser Ser Met Tyr Val
1380 1385 1390
Lys Glu Phe Leu Val Ser Ser Ser Gln Asp Gly Arg Arg Trp Thr Leu
1395 1400 1405
Phe Leu Gln Asp Gly His Thr Lys Val Phe Gln Gly Asn Gln Asp Ser
1410 1415 1420
Ser Thr Pro Val Val Asn Ala Leu Asp Pro Pro Leu Phe Thr Arg Tyr
1425 1430 1435 1440
Leu Arg Ile His Pro Thr Ser Trp Ala Gln His Ile Ala Leu Arg Leu
1445 1450 1455
Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
1460 1465
Claims (12)
- 서열번호 38로 표시되는 POL1212의 아미노산 서열을 인코딩하는 DNA.
- 제 1항의 DNA을 포함하는 발현벡터.
- 서열번호 37로 표시되는 뉴클레오타이드 서열을 가지는 제 1항의 DNA.
- 제 3항의 DNA을 포함하는 발현벡터.
- 서열번호 38로 표시되는 아미노산 서열을 가지는 변형된 돼지 인자 Ⅷ.
- 제 5항의 변형된 돼지 인자 Ⅷ와 생리적으로 허용되는 담체을 포함하는 치료학적 조성물.
- 서열번호 38의 아미노산 서열을 인코딩하는 DNA을 포유세포에서 발현시키는 단계를 포함하는 서열번호 38의 아미노산 서열을 가지는 변형된 돼지 인자 Ⅷ을 생산하는 방법.
- 제 7항에 있어서, 상기 서열번호 38의 아미노산 서열을 인코딩하는 DNA는 변형된 돼지 인자 Ⅷ 단백질이 포유세포 밖으로 방출될 수 있도록 신호 펩타이드를 인코딩하는 것을 특징으로 하는 서열번호 38의 아미노산 서열을 가지는 변형된 돼지 인자 Ⅷ을 생산하는 방법.
- 제 8항에 있어서, 상기 신호 펩타이드는 서열번호 30의 아미노산 1-19의 서열을 가지는 것을 특징으로 하는 서열번호 38의 아미노산 서열을 가지는 변형된 돼지 인자 Ⅷ을 생산하는 방법.
- 서열번호 38로 표시되는 POL1212의 아미노산 서열을 인코딩하는 DNA을 포함하는 발현벡터를 함유하고 이를 복제하는 포유세포.
- 제 10항에 있어서, 상기 DNA을 포함하는 발현벡터는 서열번호 37의 뉴클레오타이드 서열을 가지는 것을 특징으로 하는 포유세포.
- 제 11항에 있어서, 상기 포유세포는 BHK CRL-1632인 것을 특징으로 하는 포유세포.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/523,656 US6458563B1 (en) | 1996-06-26 | 2000-03-10 | Modified factor VIII |
| US09/523,656 | 2000-03-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20020081426A KR20020081426A (ko) | 2002-10-26 |
| KR100485525B1 true KR100485525B1 (ko) | 2005-04-28 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR10-2002-7011843A KR100485525B1 (ko) | 2000-03-10 | 2001-02-16 | 변형된 혈액응고인자 ⅷ |
Country Status (36)
| Country | Link |
|---|---|
| US (3) | US6458563B1 (ko) |
| EP (1) | EP1280540B1 (ko) |
| JP (1) | JP4044337B2 (ko) |
| KR (1) | KR100485525B1 (ko) |
| CN (1) | CN1191360C (ko) |
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